Preparation of new wittig reagents and their application to the synthesis of α,β-unsaturated phosphonates

Article abstract of DOI:10.1021/jo9608275

The Wittig reagent [(diethoxyphosphinyl)methylidene]triphenylphosphorane (1b) has been successfully synthesized for the first time via its phosphonium triflate salt (4a), by treating (diethoxyphosphinyl)methyl triflate with triphenylphosphine. The procedure has been applied to the synthesis of other phosphoranes and phosphonium salts. The new Wittig reagents thus synthesized were treated with various aldehydes and an activated ketone, affording the corresponding α,β-unsaturated phosphonates. Triphenylphosphorane 1b and triphenylphosphonium 4a led to both cis and trans isomers with the latter being predominant, while trans isomers were almost exclusively formed when tributyl reagents (1c and 4d) were used.

Full text of DOI:10.1021/jo9608275

J . Org. Chem. 1996, 61, 7697-7701
7697
P r ep a r a tion of New Wittig Rea gen ts a n d Th eir Ap p lica tion to th e
Syn th esis of r,â-Un sa tu r a ted P h osp h on a tes
Yibo Xu, Michael T. Flavin, and Ze-Qi Xu*
MediChem Research, Inc., 12305 South New Avenue, Lemont, Illinois 60439
Received May 6, 1996X
The Wittig reagent [(diethoxyphosphinyl)methylidene]triphenylphosphorane (1b) has been suc-
cessfully synthesized for the first time via its phosphonium triflate salt (4a ), by treating
(diethoxyphosphinyl)methyl triflate with triphenylphosphine. The procedure has been applied to
the synthesis of other phosphoranes and phosphonium salts. The new Wittig reagents thus
synthesized were treated with various aldehydes and an activated ketone, affording the corre-
sponding R,â-unsaturated phosphonates. Triphenylphosphorane 1b and triphenylphosphonium
4a led to both cis and trans isomers with the latter being predominant, while trans isomers were
almost exclusively formed when tributyl reagents (1c and 4d ) were used.
Phosphonic acids have been frequently used as suitable
isosteric and isoelectronic replacements for biologically
important phosphates such as nucleotides, phospholipids,
nucleoside polyphosphates, and sugar phosphates.1,2
Also, phosphonic acids containing an amino group in the
R-, â-, or γ-position have attracted considerable interest
as replacements for natural amino acids.3,4 These phos-
phonic acid analogues can exert their biological activity
as regulators, mediators, or enzyme inhibitors.1-4 In
addition, phosphonates have found wide application in
general organic synthesis.5-7 For example, phosphonate-
stabilized carbanions undergo Horner-Wadsworth-Em-
mons condensation with aldehydes and ketones to afford
olefins;5,6 vinyl phosphonates have been used in Diels-
Alder reactions and Michael additions, and they are also
versatile intermediates for the synthesis of hetero- and
carbocyclic compounds.7
into the dibenzyl ester followed by hydrogenolysis or
alkaline hydrolysis to remove one phenyl group followed
by enzymatic treatment with Crotalus atrox phospho-
diesterase to remove the second one.10-15 Tetraeth-
yl methylenebis(phosphonate) (2) has been used in
Horner-Wadsworth-Emmons condensations to provide
diethyl phosphonates,5,6 which can be readily hydrolyzed
by using Me3SiBr. Strongly basic reagents are gen-
erally required for such condensations and, therefore,
may not be suitable for base-sensitive aldehydes and
ketones, resulting in poor yield and the formation of side
products.16
As part of our research program, it has been of interest
to prepare phosphonate esters under less basic conditions
and execute the subsequent hydrolysis under mild condi-
tions. One reagent which meets such requirements is
[(diethoxyphosphinyl)methylidene]triphenylphosphor-
ane (1b). Moffat et al. attempted to prepare the reagent
1b by reaction of triphenylphosphine with diethyl (iodo-
methyl)phosphonate, but were not successful.9 Even
though 1b has been mentioned in review articles con-
cerning the Wittig reaction,5,6 reference to Moffat’s paper9
for synthesis and reactions of 1b has always been made.
Numerous methods have been reported in the litera-
ture for the synthesis of phosphonates, the best known
of which are the Arbuzov and Michaelis-Becker reac-
tions.8 The Wittig reagent, [(diphenoxyphosphinyl)-
methylidene]triphenylphosphorane (1a ), developed by
Moffatt et al. in 1968,9 has been applied to the synthesis
of various diphenyl phosphonates.5,6,10-15 However, the
subsequent removal of the phenyl groups is difficult and
requires either transesterification of the diphenyl ester
(RO)2P(O)CHdPPh3
(EtO)2P(O)CH2P(O)(OEt)2
1a , R ) Ph
b, R ) Et
2
X Abstract published in Advance ACS Abstracts, October 1, 1996.
(1) Engel, R. Chem. Rev. 1977, 77, 349.
(2) Klachburn, G. M.; Perree, T. D.; Rashid, A.; Bisbal, C.; Lebleu,
B. Chem. Scr. 1986, 26, 21.
(3) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem.
1991, 63, 193.
(4) O’Donnell, M. J .; Lawley, L. K.; Pushpavanam, P. B.; Burger,
A.; Bordwell, F. G.; Zhang, X.-M. Tetrahedron Lett. 1994, 35, 6421 and
references cited therein.
(5) Wadsworth, W. S., J r. Org. React. 1977, 25, 73.
(6) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(7) Minami, T.; Motoyoshiya, J . Synthesis 1992, 333.
(8) Bhattacharya, A.; Thyagarajan, G. Chem. Rev. 1981, 81, 415.
(9) J ones, G. H.; Hamamura, E. K.; Moffatt, J . G. Tetrahedron Lett.
1968, 5731.
(10) J ones, G. H.; Moffatt, J . G. J . Am. Chem. Soc. 1968, 90, 5337.
(11) Fuertes, M.; Witkowski, J . T.; Streeter, D. G.; Robins, R. K. J .
Med. Chem. 1974, 17, 642.
Trifluoromethanesulfonate (triflate) is an excellent
leaving group and has been widely used in organic
synthesis.17 Since (diethoxyphosphinyl)methyl triflate
(3a ) has been synthesized and demonstrated to react with
nucleophiles,18 it was anticipated that 3a would readily
react with triphenylphosphine to form the phosphonium
triflate salt 4a , which, in turn, would yield the ylide 1b
after treatment with a base. Herein, we would like to
communicate our method for preparation of 4a and 1b
and their analogues, as well as their application to the
synthesis of R,â-unsaturated phosphonates.
Two methods have been published for the synthesis of
(diethoxyphosphinyl)methyl triflate (3a ) from diethyl
(hydroxymethyl)phosphonate, one of which used triflic
(12) Kappler, F.; Hai, T. T.; Cotter, R. J .; Hyver, K. J .; Hampton, A.
J . Med. Chem. 1986, 29, 1030.
(13) Martin, J . C.; Verheyden, J . P. H. Nucleosides Nucleotides 1988,
7, 365.
(14) Secrist, J . A., III; Riggs, R. M.; Comber, R. N.; Montgomery, J .
A. Nucleosides Nucleotides 1992, 11, 947.
(15) Freeman, G. A.; Rideout, J . L.; Miller, W. H.; Reardon, J . E. J .
Med. Chem. 1992, 35, 3192.
(16) Gupta, A.; Sacks, K.; Khan, S.; Tropp, B. E.; Engel, R. Synth.
Commun. 1980, 10, 299.
(17) Stang, P. J .; Hanack, M.; Subramanian, L. R. Synthesis 1982,
85.
(18) Phillion, D. P.; Andrew, S. S. Tetrahedron Lett. 1986, 27, 1477.
S0022-3263(96)00827-4 CCC: $12.00 © 1996 American Chemical Society

7698 J . Org. Chem., Vol. 61, No. 22, 1996
Xu et al.
Sch em e 1
corresponding ylide 1c also reacted with aldehydes
(entries 4 and 5, Table 1), but they appeared to be more
reactive when compared with 4a and 1b, thereby requir-
ing mild reaction conditions and resulting in formation
of a higher percentage of trans isomer. For example, in
the reaction of tributylphosphorane 1c with 4-chloroben-
zaldehyde (entry 5, Table 1), the trans isomer of 5b was
exclusively produced.
Reaction with ordinary ketones such as acetophenone
was very slow under similar conditions with both phos-
phonium triflate salts (4a and 4d ) and ylides (1b and
1c). However, activated ketones such as 4-chloro-2,2,2-
trifluoroacetophenone reacted with both phosphonium
triflate salts (4a and 4d ) to afford the corresponding R,â-
unsaturated phosphonate 5g, with the two isomers being
formed in approximately a 75:25 ratio (entries 11 and
12, Table 1).
chloride in the presence of sodium hydride,18 while the
other employed triflic anhydride and lutidine.19 The
second procedure was chosen for the preparation of 3a
because triflic anhydride is less volatile than triflic
chloride and, thus, is relatively easier to handle. (Di-
methoxyphosphinyl)methyl and [bis(benzyloxy)phosphi-
nyl]methyl triflate (3b and 3c) were also prepared by the
same procedure from the corresponding hydroxyl com-
pounds (Scheme 1).
As designed, all the triflates (3a -c) reacted readily
with triphenylphosphine in CH2Cl2 at rt to afford phos-
phonium triflate salts 4a -c in ca. 80% yield (Scheme 1).
Tributylphosphine has also been demonstrated to react
with 3a , leading to the formation of 4d . Not surprisingly,
(diethoxyphosphinyl)methyl tosylate20,21 failed to react
with triphenylphosphine.
Treatment of 4a with aqueous NaOH led only to the
isolation of triphenylphosphine oxide; however, treatment
of 4a and 4d with sodium hydride in THF followed by
nonaqueous workup afforded the desired ylides 1b and
1c (Scheme 1). All the phosphonium triflate salts (4a -
d ), as well as the ylides (1b and 1c), yielded satisfactory
analytical and spectral data and were determined to be
stable upon storage at rt.
The triphenylphosphonium triflate salt 4a and ylide
1b both proved to react smoothly with a variety of aro-
matic and aliphatic aldehydes at about 100 °C to generate
R,â-unsaturated phosphonates (5a -f). These results are
presented in Table 1. In the reactions with triphen-
ylphosphonium triflate salt 4a , triethylamine was added
as a base and ylide 1b was assumed to be generated in
situ. As expected, electron-withdrawing groups acceler-
ated the reaction and electron-donating substituents
slowed the reaction (entries 2 and 6, Table 1).
The structural assignments of the trans and cis isomers
1
of 5a -f were made by analysis of H NMR data. It is
well established that the coupling constants between the
olefinic protons and phosphorus in R,â-unsaturated phos-
phonates are within the following ranges: J cis-H,H ) 8-15
Hz, J trans-H,H ) 14-18 Hz, J cis-H,P ) 10-30 Hz, J trans-H,P
) 30-50 Hz, and J gem-H,P ) 12-20 Hz.22-24 In the cases
of 5a -c, the signals due to the olefinic protons â to
phosphorus overlapped with the phenolic protons, while
the olefinic protons R to phosphorus had J cis-H,H ) J gem-H,P
) ca. 15 Hz and J trans-H,H ) J gem-H,P ) 17-18 Hz.
For compound 5d , derived from trans-cinnamaldehyde,
the two isomers (trans and cis in terms of the newly
formed double bond) were separated by silica gel column
chromatography and the cis isomer was unambiguously
assigned due to its J trans-H,P ) 50.7 Hz, and hence J cis-H,H
being 12.5 Hz and J gem-H,P being 17.4 Hz. Also, the two
olefinic protons for both isomers of 5f were clearly
assigned, since there was no interference with the
phenolic protons. Thus, J cis-H,H ) 13.0 Hz, J trans-H,P
)
53.0 Hz, and J gem-H,P ) 19.9 Hz were observed for the
cis isomer, while J trans-H,H ) 17.1 Hz, J cis-H,P ) 22.0 Hz,
and J gem-H,P ) 21.2 Hz were found for the trans isomer.
Interestingly, compound 5e, the pure trans isomer, was
the double-bond-migrated product, in which the double
bond was conjugated with the phenyl ring (â,γ-unsatur-
ated phosphonate), instead of the normal R,â-unsaturated
phosphonate. It might be hypothesized that the latter
compound was originally formed in the reaction but then
rearranged to 5e under the reaction conditions (Scheme
3), suggesting that 5e is more thermodynamically stable.
In the 1H NMR spectrum of 5e, neither geminal nor
vicinal coupling between the two olefinic protons and
phosphorus was observed. Instead, only long-range
coupling of the two olefinic protons from phosphorus was
recorded, with the J values being 7.2 and 5.1 Hz,
respectively. However, a typical geminal splitting by
phosphorus was observed for the methylene group (J gem-H,P
In contrast to the reaction of diphenyl phosphonate
ylide 1a , in which only trans R,â-unsaturated phospho-
nates were observed,9 a mixture of cis and trans isomers
were formed with both phosphonium triflate salt 4a and
ylide 1b, and the ratios of trans/cis varied from 60:40 to
80:20. However, when suitably protected nucleoside
aldehydes such as the 2′,3′-isopropylideneadenosine de-
rivative10 were treated with ylide 1b at rt, only trans
isomer 6 was formed (Scheme 2). This result was similar
to that observed for the diphenyl phosphonate ylide 1a .10
Similarly, tributylphosphonium triflate salt 4d and the
1
1
) 22.2 Hz in H NMR and J C,P ) 140.9 Hz in 13C NMR),
confirming that the CH2 group was attached to phospho-
rus. Hydrogenation of 5e led to the saturated phospho-
nate 7a (Scheme 3).
The resulting R,â-unsaturated phosphonate esters
(5a -d ,f) can be hydrogenated to afford the saturated
phosphonate esters or be easily hydrolyzed by Me3SiBr
(19) Creary, X.; Underiner, T. L. J . Org. Chem. 1985, 50, 2165.
(20) Holy, A.; Rosenberg, I. Collect. Czech. Chem. Commun. 1982,
47, 3447.
(21) Krecmerova, M.; Hrebabecky, H.; Holy, A. Collect. Czech. Chem.
Commun. 1990, 55, 2521.
(22) Kenyon, G. L.; Westheimer, F. H. J . Am. Chem. Soc. 1966, 88,
3557.
(23) Petrov, A. A.; Ionin, B. I.; Ignatyev, V. M. Tetrahedron Lett.
1968, 15.
(24) Tavs, P.; Weitkamp, H. Tetrahedron 1970, 26, 5529.

Preparation and Application of New Wittig Reagents
J . Org. Chem., Vol. 61, No. 22, 1996 7699
Ta ble 1. Rea ction of P h osp h on iu m Tr ifla te Sa lts a n d Ylid es w ith Ca r bon yl Com p u n d sa
entry no.
Wittig reagents
aldehyde
PhCHO
time (h)
yieldb (%)
product (trans:cisc)
1
2
3
4
5
6
7
8
9
4a
4a
1b
4d
1c
4a
4a
4a
1b
4a
4a
4d
20
18
4
6
6
40
20
6
4
6
75
78
68
72
78
50
57d
78
68
31e
34
34
PhCHdCHP(O)(OEt)2 (5a ) (70:30)
4-ClC6H4CHdCHP(O)(OEt)2 (5b) (70:30)
5b (86:14)
4-ClC6H4CHO
4-ClC6H4CHO
4-ClC6H4CHO
4-ClC6H4CHO
4-MeOC6H4CHO
trans-PhCHdCHCHO
PhCH2CHO
5b (96:4)
5b (100:0)
4-MeOC6H4CHdCHP(O)(OEt)2 (5c) (80:20)
PhCHdCHCHdCHP(O)(OEt)2 (5d ) (60:40)
PhCHdCHCH2P(O)(OEt)2 (5e) (100:0)
5e (100:0)
CH3(CH2)3CHdCHP(O)(OEt)2 (5f) (75:25)
4-ClC6H4C(CF3)dCHP(O)(OEt)2 (5g) (75:25)f
5g (75:25)f
PhCH2CHO
10
11
12
CH3(CH2)3CHO
4-ClC6H4COCF3
4-ClC6H4COCF3
20
16
a
b
See the Experimental Section for detailed reaction conditions. In all the reactions, the starting aldehydes had not been completely
consumed and were recovered. c The isomers refer to the newly formed double bond and were determined by H NMR. The two isomers
(trans and cis) were separated by silica gel column chromatography, and the yield was the combined one. e Some products might be lost
during the purification. f The ratio was Z/E isomers.
1
d
Sch em e 2
Sch em e 4
Analytical TLC was carried out on precoated plates (silica gel
60 F254 from EM Science), and components were visualized
with UV light and/or stained with iodine. Column chroma-
tography was performed with silica gel 60 (70-230 mesh from
EM Science). All chemical reagents and anhydrous solvents
were purchased from Aldrich Chemical Co.
Gen er a l P r oced u r es for Syn th esis of (Dia lk oxyp h os-
p h in yl)m eth yl Tr ifla tes 3a -c. To a stirred solution of
dialkyl (hydroxymethyl)phosphonate (30.6 mmol) and 2,6-
lutidine (37.6 mmol) in anhydrous CH2Cl2 (50 mL) at -50 °C
under N2 was added trifluoromethanesulfonic anhydride (35.5
mmol) dropwise. The resulting mixture was allowed to warm
to 0 °C over a period of 1.5 h, whereupon the dark brown
solution was diluted with ether (300 mL). The precipitates
formed were removed by filtration. The ethereal solution was
successively washed with water, 1 N HCl, and brine and then
dried over Na2SO4. After concentration, a yellow oil was
obtained, which was used in the next step without further
purification.
Sch em e 3
(Dieth oxyp h osp h in yl)m eth yl tr ifla te (3a ):18 9.0 g (98%
yield); 1H NMR (CDCl3) δ 1.39 (t, J ) 7.1 Hz, 6 H), 4.27-4.24
(m, 4 H), 4.64 (d, J ) 8.8 Hz, 2 H).
(Dim eth oxyp h osp h in yl)m eth yl tr ifla te (3b): 4.9 g (67%
yield). 1H NMR (CDCl3) δ 3.89 (d, J ) 8.3 Hz, 6 H), 4.65 (d,
J ) 8.8 Hz, 2 H).
[Bis(ben zyloxy)p h osp h in yl]m eth yl tr ifla te (3c): 8.3 g
(65% yield); 1H NMR (CDCl3) δ 4.45 (d, J ) 9.0 Hz, 2 H), 5.10
(m, 4 H), 7.34-7.39 (m, 10 H).
Gen er a l P r oced u r e for Syn th esis of [(Dia lk oxyp h os-
p h in yl)m eth yl]tr ip h en ylp h osp h on iu m Tr ifla tes 4a -c:
To a stirred solution of triphenylphosphine (34.4 mmol) in
anhydrous CH2Cl2 (50 mL) was added (dialkoxyphosphinyl)-
methyl triflate (3a -c) (30 mmol) in anhydrous CH2Cl2 (15 mL)
dropwise at 0 °C under N2. The mixture was allowed to warm
to rt and then stirred overnight (∼16 h). The solvent was
removed under reduced pressure to about one-third of the
volume and the remaining oil triturated with ether (200 mL).
A white solid was formed and collected by filtration. After
being washed with ether (50 mL × 2), [(dialkoxyphosphinyl)-
methyl]triphenylphosphonium triflates (4a -c) were obtained
as white solids. The analytical samples were obtained by
recrystallization from ethyl acetate/hexane.
to the corresponding phosphonic acids, examples of which
are depicted in Scheme 4. The phosphonic acid 8 was a
mixture of trans and cis isomers, and the ratio was
determined to be ca. 65:35 by H NMR, which was very
similar to that of the starting ester 5b (70:30).
In conclusion, various phosphonate Wittig reagents
have been successfully synthesized and demonstrated to
react with aldehydes and activated ketones under mild
conditions. These reagents will find general application
to the synthesis of R,â-unsaturated as well as saturated
phosphonates and the corresponding phosphonic acids.
1
Exp er im en ta l Section
Chemical shifts are reported in parts per million (δ ppm)
downfield from TMS, which was used as an internal standard.

7700 J . Org. Chem., Vol. 61, No. 22, 1996
Xu et al.
[(D ie t h o x y p h o s p h in y l)m e t h y l]t r ip h e n y lp h o s p h o -
n iu m tr ifla te (4a ): 13.7 g (82% yield). mp 98-100 °C; H
column, eluting with ethyl acetate/hexane (1:1) to afford the
1
product. The ratio of cis and trans isomers was determined
1
NMR (CDCl3) δ 1.16 (t, J ) 7.1 Hz, 6 H), 3.90-4.10 (m, 4 H),
4.20 (dd, J ) 19.6, 16.1 Hz, 2 H), 7.65-7.90 (m, 15 H); MS
(CI) 414 (26.1, M - CF3SO3H + 2), 413 (100, M - CF3SO3H +
1), 367 (26.1, M - CF3SO3H-C2H5O); IR (KBr, cm-1) 1589,
1443, 1277, 1154, 1032. Anal. Calcd for C24H27F3O6P2S: C,
51.25; H, 4.84; P, 11.01; S, 5.70. Found: C, 50.89; H, 4.84; P,
10.67; S, 6.38.
by H NMR.
P r oced u r e B: Usin g Ylid e 1b or 1c. The reaction was
carried out using a procedure similar to that described above.
However, toluene was used as the solvent without addition of
triethylamine.
Dieth yl (2-p h en yleth en yl)p h osp h on a te (5a ): colorless
1
liquid; H NMR (CDCl3) δ for cis isomer (minor) 1.18 (t, J )
[(D i m e t h o x y p h o s p h i n y l)m e t h y l]t r i p h e n y lp h o s -
p h on iu m tr ifla te (4b): 13.3 g (83% yield); mp 149-151 °C;
1H NMR (CDCl3) δ 3.62 (d, J ) 11.6 Hz, 6 H), 4.26 (dd,
7.1 Hz, 6 H), 4.00 (apparent quintet, J ) 7.2 Hz, 4 H), 5.81
(dd, J ) 15.8, 12.3 Hz, 1 H), 7.15-7.75 (m, 6 H); δ for trans
isomer (major)25 1.36 (t, J ) 7.1 Hz, 6 H), 4.14 (apparent
quintet, J ) 7.3 Hz, 4 H), 6.26 (apparent t, J ) 17.5 Hz, 1 H),
7.15-7.75 (m, 6 H); IR (neat, cm-1) 1617, 1246, 1053, 1028;
MS (CI) 242 (12.0, M + 2), 241 (100, M+).
J ) 19.9, 16.1 Hz, 2 H), 7.65-7.88 (m, 15 H); IR (KBr, cm-1
)
1589, 1443, 1273, 1154, 1038; MS (CI) 386 (21.7, M -
CF3SO3H+2), 385 (100, M - CF3SO3H + 1), 353 (35.7, M -
CF3SO3H - CH3O). Anal. Calcd for C22H23F3O6P2S: C, 49.44;
H, 4.34; P, 11.59; S, 6.00. Found: C, 49.06; H, 4.23; P, 11.29;
S, 6.19.
Diet h yl
[2-(4-ch lor op h en yl)et h en yl]p h osp h on a t e
(5b): colorless liquid; 1H NMR (CDCl3) δ for cis isomer (minor)
1.20 (t, J ) 7.0 Hz, 6 H), 4.00 (apparent quintet, J ) 7.1 Hz,
4 H), 5.81 (apparent t, J ) 15.2 Hz, 1 H), 7.10-7.65 (m, 5 H);
δ for trans isomer (major) 1.34 (t, J ) 7.2 Hz, 6 H), 4.12
(apparent quintet, J ) 7.0 Hz, 4 H), 6.22 (apparent t, J ) 17.3
Hz, 1 H), 7.10-7.65 (m, 5 H); IR (neat, cm-1) 1618, 1246, 1053,
1028; MS (CI) 277 and 275 (31.4, 100, M + 1), 276 and 274
(4.8, 13.4, M+).
[[Bis(b en zyloxy)p h osp h in yl]m et h yl]t r ip h en ylp h os-
p h on iu m t r ifla t e (4c): 17.3 g (84% yield); mp 78-81 °C;
1H NMR (CDCl3) δ 4.30 (dd, J ) 20.1, 16.1 Hz, 2 H), 4.88
(m, 4 H), 7.17-7.79 (m, 25 H); IR (KBr, cm-1) 1732, 1589,
1439, 1366, 1275, 1217, 1155, 1034; MS (FAB) 537 (100, M -
CF3SO3H + 1). Anal. Calcd for C34H31F3O6P2S: C, 59.48; H,
4.55; P, 9.02; S, 4.67. Found: C, 59.48; H, 4.53; P, 8.59; S,
4.87.
Diet h yl [2-(4-m et h oxyp h en yl)et h en yl]p h osp h on a t e
(5c): colorless liquid; 1H NMR (CDCl3) δ for cis isomer (minor)
1.23 (t, J ) 7.1 Hz, 6 H), 3.83 (s, 3 H), 4.03 (apparent quintet,
J ) 7.3 Hz, 4 H), 5.65 (apparent t, J ) 14.9 Hz, 1 H), 6.90-
7.55 (m, 5 H); δ for trans isomer (major)22 1.35 (t, J ) 7.1 Hz,
6 H), 3.83 (s, 3 H), 4.13 (apparent quintet, J ) 7.1 Hz, 4 H),
6.09 (apparent t, J ) 18.2 Hz, 1 H), 6.90-7.55 (m, 5); IR (neat,
cm-1) 1605, 1258, 1175, 1030; MS (CI) 272 (26.2, M + 2), 271
(100, M + 1), 270 (19.0, M+).
Dieth yl (1,2-cis-3,4-tr a n s-4-ph en ylbu ta-1,3-dien yl)ph os-
p h on a te (cis-5d ): pale yellow liquid; 1H NMR (CDCl3) δ 1.36
(t, J ) 7.1 Hz, 6 H), 4.13 (apparent quintet, J ) 7.1 Hz, 4 H),
5.58 (dd, J ) 17.4, 12.5 Hz, 1 H), 6.78 (d, J ) 15.4 Hz, 1 H),
7.02 (dt, J ) 50.7, 12.2 Hz, 1 H), 7.3-7.5 (m, 5 H), 7.82 (ddt,
J ) 15.0, 11.9, 1.5 Hz, 1 H); UV (MeOH) λmax 297 (38,800)
nm; IR (neat, cm-1) 1626, 1584, 1244, 1051, 1026; MS (CI) 268
(18.8, M + 2), 267 (100, M + 1), 266 (9.0, M+).
[(Diet h oxyp h osp h in yl)m et h yl]t r ib u t ylp h osp h on iu m
Tr ifla te (4d ). The compound 4d was synthesized by a
procedure similar to that described above. Tri-n-butylphos-
phine, instead of triphenylphosphine, was used. From 1 g
(33.3 mmol) of 3a and 0.8 g (40 mmol) of tri-n-butylphosphine
was obtained 1.1 g (72% yield) of a pale yellow oil: 1H NMR
(CDCl3) δ 0.98 (t, J ) 7.0 Hz, 9 H), 1.38 (t, J ) 7.0 Hz, 6 H),
1.52 (m, 12 H), 2.37 (m, 6 H), 3.09 (dd, J ) 19.5, 15.7 Hz, 2
H), 4.21 (apparent quintet, J ) 7.2 Hz, 4 H); IR (KBr, cm-1
)
1467, 1395, 1262, 1155, 1022; MS(CI) 354 (30.2, M - CF3SO3H
+ 2), 353 (100, M - CF3SO3H + 1).
[(Diet h oxyp h osp h in yl)m et h ylid en e]t r ip h en ylp h os-
p h or a n e (1b). To a stirred suspension of NaH (50 mg, 1.25
mmol, washed with hexane) in anhydrous THF (2 mL) was
added triphenylphosphonium triflate salt 4a (300 mg, 0.53
mmol) in anhydrous THF (2 mL) at 0 °C under N2. The
resulting mixture was stirred at 0 °C for 0.5 h. The solvent
was then removed at reduced pressure and the residue
extracted with anhydrous CH2Cl2. After concentration of the
extracts, a colorless oil was obtained, which was then tritu-
rated with hexane to yield an off-white solid (180 mg, 83%
yield). An analytical sample was obtained by repetitive
trituration with hexane: mp 73-75 °C; 1H NMR (CDCl3) δ
1.12 (t, J ) 7.1 Hz, 6 H), 1.27 (d, J ) 7.5 Hz, 1 H), 3.86
(apparent quintet, J ) 10.5 Hz, 4 H), 7.40-7.74 (m, 15 H);
MS (CI) 414 (27.2, M + 2), 413 (100, M + 1), 412 (32.9, M+),
367 (38.9, M - C2H5O); IR (KBr, cm-1) 1587, 1483, 1433, 1204,
1101, 976. Anal. Calcd for C23H26O3P2: C, 66.99; H, 6.35; P,
15.02. Found: C, 67.25; H, 6.57; P, 14.75.
[(Die t h oxyp h osp h in yl)m e t h ylid e n e ]t r ib u t ylp h os-
p h or a n e (1c). The procedure used for preparation of 1b
decribed above was followed for synthesis of 1c. Thus, from
tributylphosphonium triflate salt 4d (100 mg, 0.20 mmol) and
NaH (20 mg, 0.40 mmol, washed with hexane) in anhydrous
THF (2 mL) was obtained 60 mg (85% yield) of crude product,
which was used in the reaction with aldehydes without further
purification: 1H NMR (CDCl3) δ 0.93 (t, J ) 7.0 Hz, 9 H), 1.30
(m, 7 H), 1.38 (m, 12 H), 1.78 (m, 6 H), 4.21 (m, 4 H).
Gen er a l P r oced u r es for Syn th esis of r,â-Un sa tu r a ted
P h osp h on a tes. P r oced u r e A: Usin g P h osp h on iu m Tr i-
fla te Sa lt 4a or 4d . To a stirred solution of aldehyde (1.20
mmol) in anhydrous toluene (5 mL) and DMF (1 mL) was
added [(diethoxyphosphinyl)methyl]triphenylphosphonium
triflate (4a ) or 4d (1.80 mmol) at rt under N2, followed by
addition of triethylamine (7.20 mmol). The resulting mix-
ture was slowly heated to 100 °C (for 4a ) and 70 °C (for 4d ).
The reaction was monitored by TLC analysis. After the
mixture was stirred at that temperature for a period of time
indicated in Table 1, the solvents were removed under reduced
pressure and the residue was chromatographed on a silica gel
Dieth yl (1,2:3,4-tr a n s,tr a n s-4-p h en ylbu ta -1,3-d ien yl)-
ph osph on ate (tr a n s-5d): pale yellow liquid; 1H NMR (CDCl3)
δ 1.35 (t, J ) 7.1 Hz, 6 H), 4.12 (apparent quintet, J ) 7.2 Hz,
4 H), 5.80 (dd, J ) 18.9, 16.7 Hz, 1 H), 6.84 (m, 2 H), 7.16-
7.46 (m, 6 H); UV (MeOH) λmax 294 (43,400) nm; IR (neat, cm-1
)
1626, 1589, 1244, 1054, 1022; MS (CI) 268 (34.2, M + 2), 267
(100, M + 1), 266 (29.1, M+).
Diet h yl
(tr a n s-3-p h en yl-2-p r op en yl)p h osp h on a t e
1
(5e): colorless liquid; H NMR (CDCl3) δ 1.32 (t, J ) 7.1 Hz,
6 H), 2.77 (ddd, J ) 22.2, 7.6, 1.1 Hz, 2 H,), 4.12 (apparent
quintet, J ) 7.3 Hz, 4 H), 6.15 (apparent dq, J ) 14.9, 7.2 Hz,
1 H), 6.53 (dd, J ) 15.8, 5.1 Hz, 1 H), 7.22-7.40 (m, 5 H); 13
C
3
1
NMR (CDCl3) δ 16.3 (d, J C,P ) 5.7 Hz), 31.0 (d, J C,P ) 140.9
2
2
Hz), 62.0 (d, J C,P ) 6.9 Hz), 118.8 (d, J C,P ) 12.6 Hz), 127.6
and 128.6 (2 s), 134.7 (d, 3J C,P ) 14.9 Hz), 136.9 (d, 4J C,P ) 3.4
Hz); IR (neat, cm-1) 1651, 1599, 1250, 1024; MS (CI) 256 (13.7,
M + 2), 255 (100, M + 1), 254 (29.1, M+).
Dieth yl 1-h exen ylp h osp h on a te (5f): colorless liquid; 1H
NMR (CDCl3) δ for cis isomer (minor) 0.91 (t, J ) 7.0 Hz, 3
H), 1.31 (t, J ) 7.1 Hz, 6 H), 1.24-1.45 (m, 4 H), 2.52 (m, 2
H), 4.07 (apparent quintet, J ) 7.3 Hz, 4 H), 5.58 (dd, J )
19.9, 13.0 Hz, 1 H), 6.47 (ddt, J ) 53.0, 13.0, 7.6 Hz, 1 H); δ
for trans isomer (major) 0.89 (t, J ) 7.0 Hz, 3 H), 1.31 (t, J )
7.1 Hz, 6 H), 1.24-1.45 (m, 4 H), 2.21 (m, 2 H), 4.06 (apparent
quintet, J ) 7.3 Hz, 4 H), 5.63 (dd, J ) 21.2, 17.1 Hz, 1 H),
6.78 (ddt, J ) 22.0, 17.1, 6.7 Hz, 1 H); IR (neat, cm-1) 1632,
1248, 1028; MS (CI) 222 (13.2, M + 2), 221 (100, M + 1).
Dieth yl [2-(4-ch lor op h en yl)-3,3,3-tr iflu or o-1-p r op en yl]-
1
p h osp h on a te (5g): colorless liquid; H NMR (CDCl3) δ for
Z-isomer (major) 1.17 (t, J ) 7.1 Hz, 6 H), 3.78-4.01 (m, 4 H),
6.55 (dq, J ) 12.3, 1.2 Hz, 1 H), 7.36, 7.40 (AB type, J AB ) 8.6
Hz, 4 H); δ for E-isomer (minor) 1.38 (t, J ) 7.1 Hz, 6 H), 4.22
(25) Xu, Y.; J in, X.; Huang, G.; Huang, Y. Synthesis 1983, 556.

Preparation and Application of New Wittig Reagents
J . Org. Chem., Vol. 61, No. 22, 1996 7701
(dq, J ) 7.2, 7.4 Hz, 4 H), 6.27 (d, J ) 8.4 Hz, 1 H), 7.35, 7.37
(AB type, J AB ) 8.4 Hz, 4 H); IR (neat, cm-1) 1643, 1595, 1256,
1134, 1024; MS (CI) 345 and 343 (33.3, 100, M + 1).
Dieth yl (2-P h en yleth yl)p h osp h on a te (7b). Compound
5a (30 mg) was hydrogenated using the same procedure
described above to afford 7b quantitatively: 1H NMR
(CDCl3) δ 1.32 (t, J ) 7.1 Hz, 6 H), 2.11 (m, 2 H), 2.85 (m,
2 H), 4.09 (apparent quintet, J ) 7.4 Hz, 4 H), 7.21-7.29
(m, 5 H).
9-[5,6-Did eoxy-6-(d iet h oxyp h osp h in yl)-2,3-O-isop r o-
p ylid en e-â-D-r ibo-h ex-5-en ofu r a n osyl]a d en in e (6). To a
stirred solution of 2′,3′-isopropylideneadenosine (200 mg, 0.65
mmol) and pyridinium trifluoroacetate (62 mg, 0.32 mmol) in
dry DMSO (5 mL) at rt under N2 was added a solution of DCC
(400 mg, 1.95 mmol) in dry DMSO (1 mL). The reaction
mixture was stirred at rt for 8 h, and then additional DCC
(300 mg, 1.46 mmol) and pyridinium trifluoroacetate (38 mg,
0.20 mmol) were added. The reaction mixture was stirred
overnight, and TLC analysis indicated the completion of the
reaction. After removal of the resulting DCU by filtration,
crude 1b (400 mg, 0.98 mmol) was added into the filtrate. The
resulting mixture was stirred at rt for 36 h, then diluted with
ethyl acetate (50 mL), washed with water (3 × 30 mL), and
dried over Na2SO4. A pale brown solid (71 mg, 25% yield) was
obtained after silica gel column chromatography and elution
with 5% methanol in CH2Cl2: mp 85-89 °C, 1H NMR (DMSO-
d6) δ 1.15 (t, J ) 6.9 Hz, 3 H), 1.16 (t, J ) 7.1 Hz, 3 H), 1.35
(s, 3 H), 1.56 (s, 3 H), 3.82 (apparent quintet, J ) 7.8 Hz, 4
H), 4.81 (br, 1 H), 5.19 (dd, J ) 6.3 Hz, J ) 3.3 Hz, 1 H), 5.56
(d, J ) 5.7 Hz, 1 H), 5.72 (t, J ) 18.6 Hz, 1 H), 6.28 (s, 1 H),
6.65 (ddd, J ) 22.2 Hz, J ) 16.7 Hz, J ) 5.6 Hz, 1 H), 7.35 (s,
2 H), 8.15 and 8.30 (2 s, 2 H); IR (KBr, cm-1) 3337 (m, NH2),
1642, 1597, 1211, 1028; MS (CI) 441 (21.3, M + 2), 440 (100,
M + 1), 439 (2.5, M+).
[2-(4-Ch lor op h en yl)eth en yl]p h osp h on ic a cid (8). To a
stirred solution of 5b (50 mg, 0.18 mmol) in dry CH2Cl2 (5 mL)
at rt under N2 was added bromotrimethylsilane (280 mg, 1.8
mmol) dropwise. The reaction mixture was stirred for 2 h.
The volatile materials were then removed under vacuum, and
the residue was dissolved in water (5 mL) and stirred for 10
min. The aqueous solution was washed with ether and
coevaporated with MeOH to dryness, affording a white solid
(42 mg, 94% yield): mp >300 °C; 1H NMR (D2O) δ for cis
isomer (minor) 6.03 (dd, J ) 14.4, 10.5 Hz, 1 H), 6.81 (dd, J )
40.5, 14.4 Hz, 1 H), 7.38, 7.79 (AB type, J AB ) 8.7 Hz, 4 H); δ
for trans isomer (major) 6.54 (dd, J ) 17.7, 13.5 Hz, 1 H), 6.99
(t, J ) 18.2 Hz, 1 H), 7.41, 7.53 (AB type, J AB ) 8.7 Hz, 4 H);
IR (KBr, cm-1) 3424, 1665, 1491, 1368, 1090, 978; MS (FAB)
219 and 217 (39.0, 100, M+).
Ack n ow led gm en t. The work described herein was
financially supported by a Phase I Small Business
Innovation Research (SBIR) Grant (1R43 AI38205) from
the National Institutes of Health.
Dieth yl (3-P h en ylp r op yl)p h osp h on a te (7a ). A solution
of compound 5e (30 mg) in ethanol (5 mL) was hydrogenated
over 10% Pd/C (5 mg) at atmospheric pressure. The mixture
was vigorously stirred at rt for 3 h, whereupon the catalyst
was removed by filtration and the filtrate concentrated under
reduced pressure to afford 7a as a colorless oil (30 mg, 99%
yield): 1H NMR (CDCl3) δ 1.30 (t, J ) 7.1 Hz, 6 H), 1.69-1.77
(m, 2 H), 1.91-1.94 (m, 2 H), 2.69 (t, J ) 7.5 Hz, 2 H), 4.04-
4.10 (m, 4 H), 7.16-7.30 (m, 5 H).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
all new compounds and known compounds where NMR data
were not available, as well as 13C NMR spectrum for 5e (26
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
masthead page for ordering information.
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