Efficient syntheses of (α-fluoropropargyl)phosphonate esters

Full text of DOI:10.1021/jo9602027

J . Org. Chem. 1996, 61, 5159-5164
5159
â,γ-unsaturated R-fluoro phosphonate esters (e.g., 3 or
4). The nucleophilic nature of -CH(F)P(O)(OEt)2 pre-
Efficien t Syn th eses of
(r-F lu or op r op a r gyl)p h osp h on a te Ester s
Farid Benayoud, Daniel J . deMendonca,
Cheryl A. Digits, George A. Moniz,
Tanya C. Sanders, and Gerald B. Hammond*,†
Department of Chemistry, University of Massachusetts
Dartmouth, North Dartmouth, Massachusetts 02747-2300
Received J anuary 31, 1996
The utilization of a phosphonate group as a phosphate
mimic in biological systems is a well-established strategy1
that has been enhanced by fluorine substitution on the
R-carbon of phosphonates.2 Fluorine increases the ef-
fectiveness of phosphate mimetics due to the isosteric and
isoelectronic character of the resulting fluoromethylene-
phosphonate derivative, viz. a viz. the parent phosphate.
The importance of fluorine substitution in phosphonates
has been underscored by numerous reported syntheses
of R-fluoroalkanephosphonates 1, the majority of which
utilized the diethyl ester of (fluoromethylene)phosphonate-
(+M-CHF-P(O)(OEt)2) as a fluorine-containing synthon.3
Notable exceptions are the synthesis of R-fluoroalkane-
phosphonates via electrophilic fluorination,4 and (diethyl-
amidosulfur trifluoride (DAST) promoted replacement of
(R-hydroxybenzyl)phosphonates.5 Recently, the discovery
of antiviral and antitumor activity in certain cyclic and
acyclic unsaturated phosphonate derivatives such as 26
has sparked interest in the synthesis of â,γ-unsaturated
alkenephosphonates. It is plausible to speculate that
R-fluorine substitution may render unsaturated phos-
phonate analogues with enhanced biological activity.
However, in clear contrast to the many syntheses of 1,
there is no literature precedence for the preparation of
cludes its general use in coupling reactions with sp2 or
sp carbons. Clearly, there is a need for a new fluorinated
molecular building block for the introduction of fluorine
on the R-carbon of â,γ-unsaturated phosphonates. We
postulated that R-fluoroalkynephosphonate 3 could fill
this gap by serving not only as a convenient starting
material for the preparation of more complex R-fluoro
phosphonates but also as a fluorinated scaffold for the
synthesis of fluorine-containing organic molecules. For
example, the alkyne platform in 3 can be considered a
masked alkene or ketone, and the phosphonate group on
the R-carbon could help stabilize the generation of a
carbanion from 3 for use in condensation, addition, or
alkylation reactions.
In a preliminary communication,7 we reported the first
preparation of 3 (R1 ) Me, R2 ) H, R3 ) Et) via
regiospecific fluorination of the corresponding R-hydroxy
phosphonate 7. By using a propargylic moiety, we
avoided the rearrangement associated with fluorination
of allylic alcohols using DAST.5 In line with our objec-
tives regarding the use of 3 as a fluorinated synthon, we
showed that partial hydrogenation of the triple bond in
3 yielded the hitherto unknown fluoroalkenephosphonate
4. We now report an improved preparation of R-fluoro-
alkynephosphonates that can accommodate various
alkynes and phosphorus substrates. In addition, a new
example that previews the synthetic potential of R-fluo-
roalkynephosphonates as an effective fluorine-containing
synthon will be presented.
† Henry Dreyfus Teacher-Scholar 1996.
(1) Barton, D. H. R.; Ge´ro, S. D.; Quiclet-Sire, B.; Samadi, M. J .
Chem. Soc., Chem. Commun. 1989, 1000-1001 and references therein.
(2) Blackburn, M. J .; Kent, D. E.; Kolkmann, F. J . Chem. Soc.,
Perkin Trans. 1 1984, 1119-1125. Blackburn, M. J .; Brown, D.; Martin,
S. J .; Parratt, M. J . J . Chem. Soc., Perkin Trans. 1 1987, 181-186.
Chambers, R. D.; J aouhari, R.; O’Hagan D. J . Chem. Soc., Chem.
Commun. 1988, 1169-1170. Chambers, R. D.; J aouhari, R.; O’Hagan,
D. Tetrahedron 1989, 45, 5101-5108. Chambers, R. D.; O’Hagan, D.;
Lamont, R. B.; J ain, S. C. J . Chem. Soc., Chem. Commun. 1990, 1053-
1054. Lindell, S. D.; Turner, R. M. Tetrahedron Lett. 1990, 31, 5381-
5384. Halazy, S.; Ehrhard, A.; Danzin, C. J . Am. Chem. Soc. 1991,
113, 315-317. Thatcher, G. R.; Campbell, A. S. J . Org. Chem. 1993,
58, 2272-2281 and references therein.
(3) Obayashi, M.; Ito, E.; Matsui, K.; Kondo, K Tetrahedron Lett.
1982, 23, 2323-2326. Burton, D. J .; Ishihara, T.; Maruta, M. Chem.
Lett. 1982, 755-758. Blackburn, M. J .; Parratt, M. J . J . Chem. Soc.,
Perkin Trans. 1 1986, 1417. Blackburn, M. J .; Parratt, M. J . J . Chem.
Soc., Perkin Trans. 1 1986, 1425-1430. Blackburn, G. M.; Rashid, A.
J . Chem. Soc., Chem. Commun. 1988, 317-319. Blackburn, G. M.;
Rashid, A. J . Chem. Soc., Chem. Commun. 1989, 40-41. Burton, D.
J .; Sprague, L. G. J . Org. Chem. 1988, 53, 1523-1527. Burton, D. J .;
Sprague, L. G. J . Org. Chem. 1989, 54, 613-617. Yang, Z.; Burton, D.
J . Tetrahedron Lett. 1991, 32, 1019-1022. Yang, Z.; Burton, D. J . J .
Org Chem. 1992, 57, 4676-4683. Martin, S. F.; Dean, D. W.; Wagman,
A. S. Tetrahedron Lett. 1992, 33, 1839-1842. Patois, C.; Savignac, P.
J . Chem. Soc., Chem. Commun. 1993, 1711-1712. Berkowitz, D. B.;
Eggen, M.; Shen, Q.; Sloss, D. G. J . Org Chem. 1993, 58, 6174-6176.
Berkowitz, D. B.; Shen, Q.; Maeng, J . H. Tetrahedron Lett. 1994, 35,
6445-6448. Lequeux, T. P.; Percy, J . M. Synlett 1995, 361-362.
Matulic-Adamic, J .; Haeberli, P.; Usman, N. J . Org Chem. 1995, 60,
2563-2569.
Resu lts a n d Discu ssion
If R-fluoroalkynephosphonate 3 was to be considered
a fluorinated synthon, then a short and high yield
synthesis of it must be available. The two most impor-
tant steps in the synthesis of 3 are the introduction of
the phosphonate group and of the fluorine atom. Our
initial approach to the introduction of the phosphonate
group relied on a base-promoted 1,2 O to C phosphorus
migration8 of propargylic phosphate 6 to yield 7 (Scheme
1). Phosphate 6 could be easily obtained by phosphoryl-
ation of readily available alkynol 5 using an electrophilic
phosphorus reagent such as diethyl chlorophosphate. We
accomplished this task in one vessel without isolating the
(4) Differding, E.; Duthaler, R. O.; Krieger, A.; Ruegg, G. M.; Schmit,
C. Synlett 1991, 395-396.
(5) Blackburn, M. J .; Kent, D. E. J . Chem. Soc., Chem. Commun.
1981, 511-513. Blackburn, M. J .; Kent, D. E. J . Chem. Soc., Perkin
Trans. 1 1986, 913-917. DAST action on secondary R-hydroxyalkane-
phosphonates promoted dehydration rather than fluorine substitution.
(6) Megati, S.; Phadtare, S.; Zemlicka, J . J . Org. Chem. 1992, 57,
2320-2327.
(7) Sanders, T. C.; Hammond, G. B. J . Org Chem. 1993, 58, 5598-
5599.
(8) Sturtz, G.; Corbel, B. C.R. Acad. Sci. Paris 1973, 276, 1807.
Hammerschmidt, F.;Vo¨llenkle, H. Liebigs Ann. Chem. 1986, 2053-
2064.
S0022-3263(96)00202-2 CCC: $12.00 © 1996 American Chemical Society

5160 J . Org. Chem., Vol. 61, No. 15, 1996
Notes
Ta ble 1. P r ep a r a tion of r-Hyd r oxy P h osp h on a tes 7a -j
a n d r-F lu or o P h osp h on a tes 3a -j
Sch em e 1
% yielda
entry
R1
Me
TMS
Ph
Me
Et
Ph
n-C5H11
Ph
Ph
n-C5H11
R2
R3
7
3
a
b
c
d
e
f
g
h
i
H
H
H
Et
Me
Me
H
H
H
Et
Et
Et
Et
Et
Et
Et
Bu
55b
74
73
78
76
73
83
83
77
74
85
80
94
67c
86d
91
94
89
79
76
CH2CH(Et)C4H9
CH2CH(Et)C4H9
j
H
a
b
Isolated yield. Obtained via phosphate-phosphonate Meth-
odology. c Based on 31P NMR. Based on 19F NMR.
d
alkynyl ketones 8d ,e, the reaction did not go to comple-
tion, even after being stirred for several days; in these
cases, replacement of KF‚2H2O with NaN(TMS)2 in THF
led to complete reactions in 1-3 h. When R1 ) TMS (8b),
use of potassium fluoride led to desilylation. This
problem was circumvented by substituting diethylamine
in ether.13 Overall, the phosphite addition was much
more efficient than the phosphate-phosphonate protocol,
with isolated yields ranging from 73 to 83% (Table 1).
No traces of a 1,4 addition product could be detected. The
reaction was very easy to carry out, and it could be scaled
up to molar amounts. R-Hydroxy phosphonates were
stable at room temperature but thermally labile, yielding,
in some cases (e.g., 7c and 7f), peaks in the GC-MS
spectra that corresponded to triethyl phosphate and the
starting aldehyde. R-Hydroxy phosphonate 7 suffered
gradual decomposition in silica or alumina chromatog-
raphy, and in some cases (e.g., 7e,h -j) the degradation
was extensive. To our satisfaction, the phosphite addi-
tion route yielded crystallizable solids14 or essentially
pure oils that could be fluorinated directly.
intermediate 6. Accordingly, the starting alkynol was
phosphorylated using LDA in toluene at -50 °C; the
resulting propargylphosphate, in the presence of excess
LDA, rearranged to give the desired hydroxyalkyne-
phosphonate 7 after mild acid workup. The efficiency of
this rearrangement depended on the substrate used.
Yields ranged from 20 to 75%. Secondary alkynol 5d
gave the lowest yield. Attempts to introduce other
substituents on the phosphorus terminus were unsuc-
cessful. For example, using diphenyl chlorophosphate,
phosphate 6k produced only phenol (81% yield) after
being treated with excess LDA. A competitive O to aryl
C migration of phosphorus, with precedence in the
literature,9 could help to explain this experimental result.
Using bis(2,2,2-trichloroethyl) chlorophosphate and alkynol
5a , the phosphate-phosphonate protocol led to an in-
tractable mixture. We speculated that the increased
electrophilicity of phosphorus, arising from the electron-
withdrawing effect of the two trichloroethyl groups, might
have promoted an initial nucleophilic attack by LDA on
the phosphorus atom rather than the expected deproton-
ation on the R-carbon.
The moderate yields and competitive side reactions
observed using the phosphate to phosphonate rearrange-
ment led us to seek an alternate preparation of R-hydroxy
phosphonate 7. We decided to reverse the polarity of the
phosphorus-containing reagent, and selected for this task
a well-known base-catalyzed addition of nucleophilic
phosphites to carbonyl substrates known as the Pudovik
reaction.10 With R,â-unsaturated carbonyl compounds
and alkoxide bases, this reaction is known to give a
mixture of products corresponding to 1,4 or 1,2 addition
of phosphite.11 In our case, we found exclusive 1,2
addition of phosphite to propargyl aldehydes and ketones
8 b-g in the presence of neat KF‚2H2O.12 With aliphatic
With an efficient synthesis of R-hydroxy phosphonate
7 in hand, we investigated the optimum conditions
needed for regiospecific fluorination and found that, at
low temperatures, use of DAST in CH2Cl2 led to the
exclusive formation of the desired R-fluoro phosphonate
3 in very good yields. Only in the case of R-fluoro
phosphonates 3d ,e were moderate yields obtained. We
attributed this outcome to the existence of two competing
processes, the dehydration of tertiary alcohols, yielding
a phosphonate enyne15 (<10%), and possibly a SN2′
fluorination through a fluoroallene intermediate, as
evidenced from 31P and 19F NMR.16 Contrary to our
experience with R-hydroxy phosphonate 7, we found that
fluoro phosphonates 3a -j were thermally stable com-
(12) Texier-Boullet, F.; Foucaud, A. Synthesis 1982, 165-166.
(13) Zimin, M. G.; Cherkasov, R. A.; Pudovik, A. N. Zh. Obshch.
Khim. 1986, 56, 977-991.
(14) Sanders, T. C.; Hammond, G. B.; Golen, J . A.; Williard, P. G.
Acta Crystallogr. in press.
(15) 4-(Diethoxyphosphinyl)-2-hexyn-4-ene: 8% by 31P NMR; 1H
NMR δ 6.99 (dq, J ) 20.0, 6.7); 31P NMR δ 16.0 (s); EIMS 216 (M+,
39), 188 (18), 160 (54), 141 (20), 106 (12), 91 (24), 81 (45), 79 (60), 78
(100), 77 (91).
(16) It has been shown that allenes can be formed from alkynes in
the presence of a nucleophile when there is a good leaving group on
the carbon R to an alkyne (see: Taylor, D. R. Chem. Rev. 1967, 67,
317-59). In addition, bimolecular nucleophilic substitution reactions
in R,â-unsaturated systems which possess significant steric hindrance
at the reactive site undergo nucleophilic attack at C3 rather than C1.
Comparison of the small 19F and 31P NMR coupling constants in the
crude product mixture suggest the occurrence of γ-fluoro substitu-
tion: 31P NMR δ 13.3 (d, J ) 4); 19F NMR δ -132 (d, J ) 3); and 31P
NMR δ 13.5 (d, J ) 3); 19F NMR δ -138 (d, J ) 3).
(9) Dhawan, B.; Redmore, D. J . Org. Chem. 1984, 49, 4018-4021.
(10) For a review, see: Pudovik, A. N.; Konovalova, I. V. Synthesis
1979, 81-96.
(11) O¨ hler, E.; Zbiral, E. Chem. Ber. 1991, 124, 175-184. O¨ hler,
E.; Zbiral, E. Liebigs Ann. Chem. 1991, 229-236.

Notes
J . Org. Chem., Vol. 61, No. 15, 1996 5161
Sch em e 2
of this and other carbon-carbon bond forming reactions
is in progress, and the results will be reported in due
course.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. All moisture sensitive reactions
were performed under a nitrogen atmosphere using dry, freshly
distilled solvents, oven-dried glassware, and magnetic stirring.
THF was distilled from Na/benzophenone. Toluene and meth-
ylene chloride (CH2Cl2) were distilled from calcium hydride. N,
N-Diisopropylamine was distilled from sodium hydroxide. Di-
ethyl phosphite was distilled prior to use. All other reagents
were used as received. All reactions were monitored using one
of the following techniques: TLC, GC, GC-MS, 31P and/or 19F
NMR. Preparative TLC was performed using E. Merck silica
pounds and moderately sensitive to silica gel chroma-
tography.
gel 60 F254
. Analytical TLC was performed using Macherey-
Nagel polygram sil G/UV254 precoated plates. Column chroma-
tography utilized silica gel, 63-200 µm (Scientific Adsorbents,
Inc.), neutral alumina, 32-63 µm (Scientific Adsorbents, Inc.),
or acidic alumina, 150 mesh, 58 Å (Aldrich). Flash chromatog-
raphy was performed using silica gel, Davisil, grade 633, 200-
425 mesh, 60 Å. Dry column chromatography was performed
using Florisil, 60-100 mesh (U.S. Silica Company). Solid phase
extraction was performed using Extract-Clean columns (silica
gel, 60 Å). Melting points are uncorrected. 1H, 19F, 31P, and
13C NMR spectra were recorded in CDCl3 at 300, 282, 121, and
75 MHz, respectively. 1H NMR spectra are referenced against
internal tetramethylsilane, 19F NMR spectra against external
CFCl3, 31P NMR spectra against 85% H3PO4, and 13C NMR
spectra against internal tetramethylsilane at δ 0.0 ppm. 31P and
19F NMR spectra were broad-band decoupled from hydrogen
nuclei. J values are given in hertz. Low-resolution EI mass
spectra were recorded with an ionization voltage of 70 eV; peaks
are reported as m/ e (percent intensity relative to base peak).
Elemental analyses were performed by Atlantic Microlab, Inc.,
Norcross, GA.
We decided to apply the newly found reaction condi-
tions to the synthesis of R-keto phosphonates, using for
this purpose, an R,â-conjugated ester (9) and diethyl
phosphite. If this approach succeeded, fluorination of the
resulting R-keto phosphonate could yield the correspond-
ing (R,R-difluoropropargyl)phosphonate in only two steps
from propargyl esters. Disappointingly, we found that
no reaction took place between propargylic esters 9a ,b
and diethyl phosphite in the presence of KF‚2H2O.
Replacing the base with NaN(TMS)2 in THF led to low
yields of bisphosphinyl ester 11a via two succesive 1,4
additions of diethyl phosphite anion to 9a (Scheme 2).
When we added a new carbon to the ester chain, as in
methyl homolog 9b, the same reaction produced mono-
and bisphosphinyl esters 10b and 11b (3:1 ratio), respec-
tively. In both cases, no traces of a 1,2 addition product
were detected.
Syn th esis of Hyd r oxy P h osp h on a te 7 fr om Alk yn ol 5.
Meth od 1 (Tw o-Step P r otocol). Rep r esen ta tive P r oced u r e
for Dieth yl (1-Hyd r oxy-2-bu tyn ep h osp h on a te (7a ). 2-Bu-
tyn-1-ol (2.4 mL, 32 mmol) was added to a well-stirred mixture
of diethyl chlorophosphate (5.6 mL, 38 mmol), NaOH (50%, 200
mL), triethylbenzylammonium chloride (4.0 g), and CH2Cl2 (100
mL). After being stirred for 1 h, the mixture was diluted with
water (1 L), the aqueous layer was back-extracted with CH2Cl2,
and the combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Kugelrohr distillation gave 6a (5.54 g, 84%) as a colorless oil:
1H NMR (60 MHz) δ 1.37 (t, J ) 7, 6H), 1.87 (t, J ) 2, 3H), 4.57
(m, 4H), 4.65 (m, 2H); EIMS 206 (M+, 2), 150 (43), 127 (8), 99
(100), 81 (25), 53 (47). Anal. Calcd for C8H15O4P: C, 46.60; H,
7.33. Found: C, 46.44; H, 7.31. To a stirred solution of 6a (6.41
g, 31.1 mmol) in toluene (75 mL) at -50 °C was added LDA
[prepared in situ from N,N-diisopropylamine (6.9 mL) and
n-BuLi (1.6 M, 29.2 mL)] in toluene (41 mL). The resulting
mixture was stirred for 50 min, and the solution was quenched
with acetic acid (1 M in Et2O, 100 mL). The gelatinous mixture
was washed with water, the aqueous layer was back-extracted
with CH2Cl2, and the combined organic layers were concen-
trated. Dry column chromatography (Florisil, ethyl acetate-
hexane gradient) produced 7a (3.17 g, 49%) as an oil which
solidified on standing: 1H NMR δ 1.36 (td, J ) 7.1, 1.8, 6H),
1.90 (dd, J ) 5.7, 2.4, 3H), 4.12-4.40 (m, 4H), 4.64 (dq, J ) 15.1,
In order to explore the feasibility of using 3 as a
synthon for the preparation of complex R-fluoro phos-
phonates, we conducted a Michael reaction utilizing 3c
and methyl acrylate. This reaction would extend the
carbon chain on the R-position of 3, introducing at the
same time a carboxylic ester group on the resulting fluoro
phosphonate 12. A preliminary experiment using NaH
in benzene at room temperature did not yield the desired
compound. Most of the starting material was recovered
unchanged. When we carried out a similar reaction using
NaN(TMS)2 in THF at 0 °C, we isolated the desired fluoro
phosphinyl ester 12 in 56% yield (96% pure by 31P NMR).
This result lent validity to our argument in support of
the role of (R-fluoropropargyl)phosphonate 3 as a fluorine-
containing synthon.
2.2, 1H), 4.83 (br s, 1H); 31P NMR δ 18.7 (s); EIMS 191 (M+
-
15, 5), 177 (32), 149 (36), 138 (31), 111 (69), 82 (100), 69 (59), 41
(33). Anal. Calcd for C8H15O4P: C, 46.60; H, 7.33. Found: C,
46.76; H, 7.37.
In conclusion, we have developed the first synthesis
of (R-fluoropropargyl)phosphonate ester 3, through the
intermediacy of R-hydroxy phosphonate 7, using a short
and efficient protocol applicable to readily available
propargyl aldehydes and ketones. An alternative prepa-
ration of R-hydroxy phosphonate 7, involving an O to C
phosphorus migration (e.g., 6 to 7), proved to be less
efficient. Finally, we have successfully explored the
functionalization at the R-carbon in (R-fluoropropargyl)-
phosphonates, via a Michael reaction. The investigation
Meth od 2 (On e-F la sk P r otocol). Rep r esen ta tive P r o-
ced u r e for 7a . LDA was prepared in situ from N,N-diisopro-
pylamine (9.0 mL, 64 mmol) and n-BuLi (1.6 M, 38 mL, 61 mmol)
in toluene (53 mL) at -50 °C. An aliquot of this LDA solution
(0.6 M, 33 mL, 20 mmol) was transferred via syringe and added
dropwise to 2-butyn-1-ol (1.2 mL, 16 mmol) in toluene (20 mL)
at -50 °C followed by diethyl chlorophosphate (2.5 mL, 18
mmol). The mixture was allowed to stir for 45 min at -50 °C
after which the remainder of the LDA solution was added
dropwise with stirring over a period of 30 min. After 1 h at -50

5162 J . Org. Chem., Vol. 61, No. 15, 1996
Notes
°C, acetic acid (1 M in diethyl ether, 50 mL) was added and the
mixture was washed with water and concentrated to give an oil
which was purified as above to furnish 7a (1.83 g, 55%).
Diet h yl 1-h yd r oxy-3-(t r im et h ylsilyl)-2-p r op yn ep h os-
p h on a te (7b) was prepared from 5b (0.625 g, 4.9 mmol)
according to method 2. Attempted purification of an aliquot
(0.62 g) of the crude product by Kugelrohr distillation ended in
partial decomposition of the 7b. Purification of another aliquot
(0.66 g) by flash chromatography (silica, hexane-ethyl acetate
1:2) provided an analytically pure sample of 7b (0.15 g, 23%):
1H NMR δ 0.15 (s, 9H) 1.36 (td, J ) 7.0, 3.6, 6H), 4.09-4.30 (m,
4H), 4.64 (d, J ) 16.9, 1H); 31P NMR δ 17.6 (s); EIMS 235 (M+
- 29, 83), 207 (22), 179 (48), 155 (35), 121 (87), 111 (100), 82
(65), 45 (57). Anal. Calcd for C10H21O4PSi: C, 45.57; H, 7.67.
Found: C, 45.69; H, 7.70.
Dieth yl 1-h yd r oxy-3-p h en yl-2-p r op yn ep h osp h on a te (7c)
was prepared from 5c (2.11 g, 16.0 mmol) according to method
1. Preliminary purification using dry column chromatography
(Florisil, ethyl acetate-hexane gradient) gave 7c (2.37 g, 75%).
Recrystallization from petroleum ether/CH2Cl2 gave 7c as short,
white needles: mp 71-72 °C; 1H NMR δ 1.34-1.40 (m, 6H),
4.23-4.35(m, 4H), 4.88 (d, J ) 16.3, 1H), 7.26-7.48 (m, 5H);
13C NMR δ 16.5, 16.4, 59.4 (d, J ) 169), 64.4, 64.5, 83.2, 88.0,
128.3, 128.8, 130.0, 131.8, 133.0; 31P NMR δ 18.1; EIMS 269
(M+, 28), 251(37), 239 (100), 211 (38), 183 (67), 159 (25), 138
(22). Anal. Calcd for C13H17O4P: C, 58.20; H, 6.40. Found: C,
58.26; H, 6.44.
To a stirred mixture of diethyl phosphite (1.3 mL, 10 mmol) and
potassium fluoride dihydrate (4.70 g, 50 mmol) at 25 °C was
added 8c (1.2 mL, 10 mmol). After 1 h, the mixture was
partitioned between Et2O (100 mL) and water (100 mL) and
stirring continued for an additional 5 min. The aqueous layer
was separated and the organic layer washed with water (3 ×
50 mL) and concentrated. The resulting oil was solidified by
introducing it into an ice bath for 2 h. Recrystallization from
petroleum ether/CH2Cl2 gave 7c (1.97 g, 73%).
Meth od 2 (Na N(TMS)2). Rep r esen ta tive P r oced u r e for
Dieth yl 1-Eth yl-1-h yd r oxy-2-bu tyn ep h osp h on a te (7d ). To
a stirred solution of diethyl phosphite (0.721 g, 5.2 mmol) in dry
THF (5.0 mL) at -78 °C was added sodium bis(trimethylsilyl)-
amide (1 M in THF, 5.2 mL, 5.2 mmol). After 30 min, this
mixture was transferred slowly dropwise to a second flask
containing a stirred solution of 8d (0.507 g, 5.3 mmol) in THF
(5.0 mL) at -78 °C. After 1 h, the reaction was slowly warmed
to room temperature over 3 h before being quenched with water
(3.0 mL). The organic layer was separated and the aqueous
layer extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated to give
7d (0.956 g, 78%) as a yellow oil (76% pure by 31P NMR).
Dieth yl 1-h yd r oxy-1-m eth yl-2-p en tyn ep h osp h on a te (7e)
was prepared from 8e (0.157 g, 1.6 mmol) according to method
2. After 3 h, the reaction was slowly warmed to room temper-
ature before being quenched with water (1.0 mL). The organic
layer was separated and the aqueous layer extracted with ethyl
acetate (3 × 25 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated to give 7e (0.290 g, 76%)
as a yellow oil (95% pure by 31P NMR). Attempts to purify 7e
by chromatography led to decomposition: 1H NMR δ 1.15 (t, J
) 7.2, 3H), 1.37 (t, J ) 7.1, 6H), 1.64 (d, J ) 15.0, 3H), 2.26 (dq,
J ) 7.5, 4.7, 2H), 4.26 (m, 4H); 31P NMR δ 21.2 (s); EIMS 205
(9), 191 (50), 177 (8), 163 (28), 138 (21), 135 (79), 111 (99), 97
(47), 83 (49), 82 (100), 81 (76).
Diet h yl 1-et h yl-1-h yd r oxy-2-b u t yn ep h osp h on a t e (7d )
was prepared from 5d (0.45 mL, 4.0 mmol) according to method
2 yielding an oil (0.189 g, 20%) which solidified upon standing:
1H NMR δ 1.10 (t, J ) 7.4, 3H), 1.37-1.32 (m, 6H), 1.81-1.86
(m, 2H), 1.88 (d, J ) 5.3, 3H), 4.18-4.29 (m, 4H); 31P NMR δ
21.4 (s); EIMS 177 (16), 149 (13), 138 (11), 121 (30), 111 (49), 97
(25), 82 (71), 67 (67), 43 (100). Anal. Calcd for C10H19O4P: C,
51.28; H, 8.18. Found: C, 51.35; H, 8.20.
Dieth yl 1-Hyd r oxy-1-m eth yl-3-p h en yl-2-p r op yn ep h os-
p h on a te (7f). Diethyl phosphite (1.2 mL, 9.3 mmol), potassium
fluoride dihydrate (0.753 g, 8.0 mmol), and 8f (0.992 g, 6.9 mmol)
were stirred for 8 h according to method 1, yielding a clear yellow
oil which solidified upon immersion in an ice bath for 2 h. The
solid was recrystallized from petroleum ether/CH2Cl2 to give 7f
(1.418 g, 73%) as white needles: mp 80-81 °C; 1H NMR δ 1.29-
1.37 (m, 6H), 1.76 (d, J ) 15.0, 3H), 4.18-4.30 (m, 4H), 4.45 (br
s, 1H), 6.95-7.14 (m, 5H); 31P NMR δ 20.6 (s); 13C NMR δ 16.6,
16.7, 25.3, 64.2, 64.3, 66.0 (d, J ) 173), 86.2, 88.1, 122.4, 122.5,
128.3, 128.7, 131.9, 131.9. Anal. Calcd for C14H19O4P: C, 59.57;
H, 6.78. Found: C, 59.49; H, 6.78.
Dieth yl 1-Hyd r oxy-2-octyn ep h osp h on a te (7g). Diethyl
phosphite (6.4 mL, 50 mmol), 8g (6.2 g, 50 mmol), and potassium
fluoride dihydrate (23.5 g, 250 mmol) were stirred for 12 h
according to method 1, yielding 7g (10.8 g, 83%) as a yellow oil
(98% pure by 31P NMR). An aliquot was further purified by
preparative TLC (silica, hexane-ethyl acetate 1:1). The band
with Rf ) 0.30 was scraped and eluted with CH2Cl2 to provide
a sample of analytical purity: 1H NMR δ 0.90 (t, J ) 7.0, 3H),
1.33-1.39 (m, 10H), 1.46-1.53 (m, 2H), 2.23-2.26 (m, 2H),
4.21-4.28 (m, 4H), 4.67 (dt, J ) 15.0, 2.1, 1H); 13C NMR δ 13.7,
16.1, 16.2, 18.6, 21.9, 27.9, 30.7, 58.6 (d, J ) 172), 74.6, 88.1;
31P NMR δ 18.8 (s); EIMS 233 (M+ - 29, 4), 205 (4), 177 (8), 138
(8), 111 (26), 82 (28), 29 (100). Anal. Calcd for C12H23O4P: C,
54.96; H, 8.77. Found: C, 54.44; H, 8.72.
Dibu tyl 1-Hydr oxy-3-ph en yl-2-pr opyn eph osph on ate (7h ).
8c (0.60 mL, 5.0 mmol) was treated with dibutyl phosphite (1.0
mL, 5.0 mmol) and potassium fluoride dihydrate (2.350 g, 25
mmol) according to Method 1. This afforded 7h (1.351 g, 83%)
as a viscous yellow-orange oil (96% pure by 31P NMR). At-
tempted purification by preparative TLC resulted in loss of
hydroxy phosphonate. 1H NMR δ 0.89 (td, J ) 7.2, 1.3, 6H),
1.35-1.44 (m, 4H), 1.62-1.70 (m, 4H), 4.20-4.27 (m, 4H), 4.92
(d, J ) 16.2, 1H), 7.27-7.46 (m, 5H); 31P NMR δ 18.2 (s).
Bis(2-eth ylh exyl) 1-Hyd r oxy-3-p h en yl-2-p r op yn ep h os-
p h on a te (7i). Bis(2-ethylhexyl) phosphite (1.7 mL, 5.0 mmol),
potassium fluoride dihydrate (2.35 g, 25 mmol), and 8c (0.60
mL, 5.0 mmol) were stirred for 1 h according to method 1.
Workup as for 7h above furnished 7i (1.68 g, 77%) as a viscous
orange oil (94% pure by 31P NMR). Attempted purification by
preparative TLC resulted in loss of hydroxy phosphonate.
1H NMR δ 0.82-0.93 (m, 12H), 1.25-1.43 (m, 18H), 4.08 - 4.16
Attem p ted Syn th esis of Dip h en yl 1-Hyd r oxy-2-bu tyn e-
p h osp h on a te (7k ). To a stirred solution of 2-butyn-1-ol (0.75
mL, 10 mmol) in dry toluene (30 mL) at -50 °C was added slowly
dropwise LDA (0.5 M, 24 mL, 12 mmol) [prepared in situ from
N,N-diisopropylamine (2.5 mL, 18 mmol) and n-BuLi (8.6 mL,
1.75 M) in toluene (19 mL)]. After 30 min, diphenyl chlorophos-
phate (2.5 mL, 12 mmol) was added and the resulting mixture
stirred for 2 h. The reaction was quenched by addition of
CF3COOH (2 M in Et2O, 10 mL), forming two layers. The
organic layer was separated and the aqueous layer extracted
with Et2O (3 × 25 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated to give an orange oil
which was purified by dry column chromatography (Florisil,
ethyl acetate-hexane gradient). This afforded 6k (2.140 g, 71%)
as a yellow oil: 1H NMR δ 1.76 (t, J ) 2.4, 3H), 4.79 (dq, J )
2.3, 10.8, 2H), 7.09-7.35 (m, 10H); 31P NMR δ 11.1 (s). To a
stirred solution of 6k (0.313 g, 1 mmol) in dry toluene (10 mL)
at -50 °C was added LDA (0.5 M, 4.4 mL, 2.2 mmol) in toluene.
This mixture was allowed to stir for 45 min, after which
CF3COOH (2 M in Et2O, 4 mL) was added. The organic layer
was separated and the aqueous layer extracted with Et2O (3 ×
20 mL). The combined organic phases were pooled, dried over
MgSO4, filtered, and concentrated. The resulting residue (0.241
g) was redissolved in Et2O (25 mL) and extracted with 10%
NaOH (3 × 20 mL), leaving 0.042 g of an unidentified residue
in the original ether layer. The combined aqueous phases were
acidified with HCl (6 M) and extracted with Et2O (3 × 20 mL).
The combined ether layers were dried over MgSO4, filtered, and
concentrated to afford phenol (0.153 g, 81%).
Syn th esis of Hyd r oxy P h osp h on a te 7 fr om P r op a r gylic
Ald eh yd es or Keton es 8. Dieth yl 1-Hyd r oxy-3-(tr im eth -
ylsilyl)-2-p r op yn ep h osp h on a te (7b). To a stirred solution of
diethylamine (0.074 g, 1.0 mmol) in anhydrous Et2O (10 mL) at
25 °C was added diethyl phosphite (0.138 g, 1.0 mmol). After 5
min of stirring, 8b (0.126 g, 1.0 mmol) was added and stirring
continued for an additional 1.5 h at 25 °C. The reaction was
quenched by the addition of water (20 mL) to the mixture. The
aqueous layer was extracted with Et2O (3 × 25 mL). The organic
layers were pooled, washed with water (3 × 5 mL), dried over
MgSO4, filtered, and concentrated to give 7b (0.195 g, 74%) as
a dark oil (97% pure by 31P NMR).
Meth od 1 (KF ‚2H2O). Rep r esen ta tive P r oced u r e for
Dieth yl 1-Hyd r oxy-3-p h en yl-2-p r op yn ep h osp h on a te (7c).

Notes
J . Org. Chem., Vol. 61, No. 15, 1996 5163
(m, 4H), 4.93 (d, J ) 16.0, 1H), 7.28 - 7.59 (m, 5H); 13C NMR δ
10.7, 10.8, 13.9, 22.8, 23.0, 23.1, 28.7, 28.7, 29.7, 29.7, 40.2, 59.3
(d, J ) 170), 69.8, 70.2, 83.8, 87.5, 128.1, 128.3, 128.5, 128.6,
131.7, 131.7; 31P NMR δ 18.1 (s).
analytically pure sample was obtained by solid phase extraction
(hexane-ethyl acetate 1:1): 1H NMR δ 1.18 (t, J ) 7.5, 3H),
1.36-1.42 (m, 6H), 1.82 (dd, J ) 22.1, 14.3, 3H), 2.26-2.37 (m,
2H), 4.22-4.36 (m, 4H); 13C NMR δ 12.5, 13.1, 16.3, 16.4, 24.1
(d, J ) 25), 64.1, 64.5, 74.6, 86.6 (dd, J ) 182, 178), 93.4; 31P
NMR δ 14.9 (d, J ) 89); 19F NMR δ -152 (d, J ) 89); EIMS 180
(3), 159 (13), 149 (7), 129 (5), 111 (23), 101 (31), 79 (100), 77
(51). Anal. Calcd for C10H18FO3P: C, 50.85; H, 7.68. Found:
C, 50.56; H, 7.53.
Dieth yl 1-Flu or o-1-m eth yl-3-ph en yl-2-pr opyn eph osph on -
a te (3f). Reaction of 7f (0.468 g, 1.7 mmol) with DAST (0.40
mL, 3.0 mmol) in CH2Cl2 (10 mL) at -50 °C for 4 h according to
the general method furnished 3f (0.429g, 91%) as an amber oil
(100% pure by 31P NMR). An analytically pure sample was
obtained by solid phase extraction (hexane-ethyl acetate 1:1):
1H NMR δ 1.37-1.42 (m, 6H), 1.93 (dd, J ) 22.0, 14.2, 3H), 4.25-
4.39 (m, 4H), 7.30-7.49 (m, 5H); 13C NMR δ 16.5, 16.6, 24.0 (d,
J ) 24), 64.4, 64.7, 83.8, 86.9 (dd, J ) 180, 179), 90.4, 121.4,
128.5, 129.5, 132.0; 31P NMR δ 14.4 (d, J ) 88); 19F NMR δ -153
(d, J ) 88); EIMS 284 (M+, 1), 255 (2), 227 (8), 147 (100), 128
(62), 109 (26), 81 (43). Anal. Calcd for C14H18FO3P: C, 59.15;
H, 6.38. Found: C, 59.24; H, 6.45.
Bis(2-eth ylh exyl) 1-Hyd r oxy-2-octyn ep h osp h on a te (7j).
Potassium fluoride dihydrate (4.70 g, 50 mmol), bis(2-ethylhexyl)
phosphite (3.3 mL, 10 mmol), and 8g (1.42 mL, 10 mmol) were
stirred according to method 1. After 5 h, CH2Cl2 (50 mL) was
added and stirring continued for an additional 10 min. The
mixture was then filtered and the solid residue washed with
CH2Cl2. The filtrate was dried over MgSO4, filtered, and
concentrated to furnish 7j (3.16 g, 74%) as a pale yellow oil (95%
pure by 31P NMR). Purification attempts by column chroma-
tography (neutral alumina, hexane-ethyl acetate 4:1) and
preparative TLC resulted in the loss of compound. 1H NMR δ
0.84-0.95 (m, 15H), 1.21-1.42 (m, 24H), 2.20-2.32 (m, 2H),
4.08-4.16 (m, 4H), 4.65 (dt, J ) 15.0, 2.14, 1H); 31P NMR δ 18.5
(s); EIMS 113 (M+ - 317, 9) 96 (18), 83 (100), 71 (23), 69 (9), 57
(41), 41 (23), 28 (27).
Gen er a l Meth od for th e Syn th esis of Dia lk yl 1-F lu or o-
2-a lk yn ep h osp h on a tes 3a -j. Rep r esen ta tive P r oced u r e
for Dieth yl 1-F lu or o-3-p h en yl-2-p r op yn ep h osp h on a te (3c).
To a stirred solution of 7c (2.80 g, 10.4 mmol) in dry CH2Cl2 (20
mL) at -78 °C was added DAST (1.6 mL, 12.5 mmol). After 1
h at -78 °C, the reaction mixture was decanted carefully into a
saturated NaHCO3 solution (50 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 50 mL). Combined organic phases
were dried over MgSO4, filtered, and concentrated to give 3c
(2.64 g, 94%) as an orange oil (92% pure by 31P NMR). An
analytically pure sample was obtained by column chromatog-
raphy (acidic alumina, hexane-ethyl acetate 4:1): 1H NMR δ
1.20-1.46 (m, 6H), 4.05-4.41 (m, 4H), 5.59 (dd, J ) 47.2, 12.1,
1H), 7.20-7.51 (m, 5H); 13C NMR δ 16.2, 16.3, 64.6, 64.7, 78.2
(dd, J ) 176, 182), 79.2, 92.5, 121.1, 128.2, 129.5, 131.8; 31P NMR
δ 11.5 (d, J ) 77); 19F NMR δ -195 (d, J ) 77); EIMS 270 (M+,
5), 214 (5), 133 (85), 114 (100), 109 (54), 91 (27), 81 (81). Anal.
Calcd for C13H16FO3P: C, 57.77; H, 5.92. Found: C, 57.79; H,
5.97.
Dieth yl 1-F lu or o-2-bu tyn ep h osp h on a te (3a ). DAST (2.9
mL, 22 mmol) was reacted with 7a (3.82 g, 18 mmol) in CH2Cl2
(50 mL) at -50 °C for 1 h, yielding 3a (3.25 g, 85%). Purification
either by Kugelrohr distillation (99 °C, 1.0 Torr) or flash column
chromatography (silica, hexane-ethyl acetate 1:1) yielded ana-
lytically pure material: 1H NMR δ 1.28-1.49 (m, 6H), 1.83-
2.02 (m, 3H), 4.20-4.33 (m, 4H), 5.31 (ddq, J ) 47.4, 11.4, 2.2,
1H); 31P NMR δ 12.2 (d, J ) 78); 19F NMR δ -196 (d, J ) 77);
EIMS 208 (M+, 3), 152 (27), 129 (23), 101 (100), 81 (97), 52 (98).
Anal. Calcd for C8H14FO3P: C, 46.16; H, 6.78. Found: C, 46.37;
H, 6.82.
Dieth yl 1-F lu or o-3-(tr im eth ylsilyl)-2-bu tyn ep h osp h on -
a te (3b). A stirred solution of 7b (0.132 g, 0.50 mmol) in CH2Cl2
(10 mL) at -78 °C was treated with DAST (0.20 mL, 1.3 mmol).
After being stirred for 30 min at -78 °C, the mixture was diluted
with Et2O (10 mL), washed with saturated NaHCO3 (3 × 10 mL),
dried over MgSO4, filtered, and concentrated to give 3b (0.106
g, 80%) as a dark oil (76% pure by 31P NMR). An analytically
pure sample was obtained by column chromatography (acidic
alumina, hexane-ethyl acetate 4:1): 1H NMR δ 0.20 (s, 9H),
1.26-1.43 (m, 6H), 4.07-4.31 (m, 4H), 5.01 (dd, J ) 47.2, 12.1,
1H); 31P NMR δ 11.1 (d, J ) 76); 19F NMR δ -196 (d, J ) 76);
EIMS 251 (M+ - 16, 8), 210 (20), 195 (46), 157 (100), 123 (58),
109 (62), 81 (75), 47 (79). Anal. Calcd for C10H20FO3PSi: C,
45.11; H, 7.51. Found: C, 45.24; H, 7.47.
Dieth yl 1-F lu or o-2-ocytn ep h osp h on a te (3g). Treatment
of 7g (2.62 g, 10 mmol) with DAST (1.6 mL, 12 mmol) following
the general method afforded, after 8 h of stirring, 3g (2.48 g,
94%) as an oil (90% pure by 31P NMR) Kugelrohr distillation
(110 °C, 7 × 10-2 Torr) furnished an analytically pure sample:
1H NMR δ 0.86-1.02 (t, J ) 7.1, 3H), 1.25-1.49 (m, 10H), 1.49-
1.55 (m, 2H), 2.25-2.43 (m, 2H), 4.21-4.46 (m, 4H), 5.32 (dd, J
) 47.3, 11.4, 1H); 13C NMR δ 13.8, 16.3, 16.4, 18.9, 22.0, 27.6,
30.8, 63.9, 64.4, 70.7, 78.04 (dd, J ) 178, 180), 94.5; 31P NMR δ
11.9 (d, J ) 77); 19F NMR δ -159 (d, J ) 77); EIMS 208 (M+
-
56, 20), 180 (8), 160 (15), 152 (22), 129 (28), 109 (87), 91 (52), 81
(100). Anal. Calcd for C12H22FO3P: C, 54.54; H, 8.33. Found:
C, 54.57; H, 8.36.
Dibu tyl 1-F lu or o-3-p h en yl-2-p r op yn ep h osp h on a te (3h ).
A mixture of 7h (0.474 g, 1.5 mmol) and DAST (0.25 mL, 1.8
mmol) in CH2Cl2 (10 mL) was allowed to stir at -78 °C for 1 h
according to the general method, affording 3h (0.434 g, 89%) as
an orange oil (75% pure by 31P NMR). An aliquot (0.102 g) was
further purified by preparative TLC (hexane-ethyl acetate 1:1).
The band with Rf ) 0.65 was scraped and eluted with CH2Cl2
to afford an analytical sample (0.018 g): 1H NMR δ 0.87-0.97
(m, 6H), 1.33-1.48 (m, 4H), 1.67-1.75 (m, 4H), 4.15-4.31 (m,
4H), 5.60 (dd, J ) 47.2, 12.1, 1H), 7.30-7.52 (m, 5H); 13C NMR
δ 13.4, 18.5, 32.4, 68.0 (dd, J ) 7, 21), 78.1 (dd, J ) 177, 182),
79.5, 92.2, 121.0, 128.3, 129.9, 131.9; 31P NMR δ 11.5 (d, J )
77); 19F NMR δ -195 (d, J ) 78); EIMS 326 (M+, 3), 270 (9),
214 (100) 213 (20), 137 (21), 133 (94), 114 (79), 57 (60), 41 (54).
Anal. Calcd for C17H24FO3P: C, 62.57; H, 7.41. Found: C,
62.59; H, 7.38.
Bis(2-eth ylh exyl) 1-Flu or o-3-ph en yl-2-pr opyn eph osph on -
a te (3i). A mixture of 7i (2.00 g, 4.6 mmol), CH2Cl2 (10 mL),
and DAST (0.80 mL, 6.0 mmol) was stirred for 1 h according to
the general method. This procedure afforded 3i (1.59 g, 79%)
as an orange oil (90% pure by 31P NMR). An aliquot (0.120 g)
was further purified by preparative TLC (hexane-ethyl acetate
1:1). The band with Rf ) 0.80 was scraped and eluted with
CH2Cl2. The resulting green oil was eluted through a short
column of silica (hexane-ethyl acetate 7:3) to provide an
analytical sample (0.090 g): 1H NMR δ 0.86-0.93 (m, 12 H),
1.29-1.43 (m, 18H), 4.13-4.19 (m, 4H), 5.60 (dd, J ) 45.9, 11.8,
1H), 7.32-7.48 (m, 5H); 13C NMR δ 10.7, 13.9, 22.8, 23.1, 28.7,
29.7, 40.2, 70.2 (dd, J ) 7, 25), 78.0 (dd, J ) 178, 182), 79.6 (dd,
J ) 5, 22), 92.2 (dd, J ) 10, 12), 121.1, 128.4, 129.4, 131.8; 31P
NMR δ 11.5 (d, J ) 77); 19F NMR δ -195 (d, J ) 78); EIMS 214
(M+ - 224, 41), 195 (13), 133 (35), 114 (33), 57 (100), 49 (87).
Anal. Calcd for C25H40FO3P: C, 68.47; H, 9.19. Found: C,
68.58; H, 9.25.
Diet h yl 1-E t h yl-1-flu or o-2-b u t yn ep h osp h on a t e (3d ).
Treatment of 7d (0.358 g, 1.5 mmol) with DAST (0.35 mL, 2.7
mmol) for 2.5 h according to the general method produced 3d
(0.198 g, 67% by 31P NMR) as an amber oil. An analytically
pure sample was obtained by solid phase extraction (hexane-
ethyl acetate 7:3): 1H NMR δ 1.15 (t, J ) 7.3, 3H), 1.34-1.41
(m, 6H), 1.96 (dd, J ) 7.0, 4.9, 3H), 2.04-2.21 (m, 2H), 4.21-
4.34 (m, 4H); 31P NMR δ 14.9 (d, J ) 88); 19F NMR δ -162 (d,
J ) 89); EIMS 236 (M+, 2), 221 (2), 188 (3), 160 (6), 127 (10),
101 (38), 79 (100), 65 (38). Anal. Calcd for C10H18FO3P: C,
50.85; H, 7.68. Found: C, 50.96; H, 7.75.
Bis(2-eth ylh exyl) 1-F lu or o-2-octyn ep h osp h on a te (3j).
To a stirred solution of DAST (0.60 mL, 4.5 mmol) in CH2Cl2
(20 mL) at -50 °C was added 7j (1.94 g, 4.5 mmol) following
the general method. The mixture was allowed to react for 1 h,
affording 3j (1.48 g, 76%) as an oil (84% pure by 31P NMR). An
analytically pure sample was obtained by column chromatog-
raphy (acidic alumina, hexane-ethyl acetate 4:1): 1H NMR δ
0.79-0.98 (m, 15H) 1.21-1.67 (m, 24H), 2.21-2.35 (m, 2H),
3.97-4.19 (m, 4H), 5.35 (ddt, J ) 48.7, 12.7, 3.7, 1H); 31P NMR
Dieth yl 1-F lu or o-1-m eth yl-2-p en tyn ep h osp h on a te (3e).
A solution of 7e (0.447 g, 1.9 mmol) and DAST (0.40 mL, 3.0
mmol) in dry CH2Cl2 (10 mL) was allowed to react for 6 h,
affording 3e (0.236 g, 86% by 19F NMR) as a clear yellow oil. An

5164 J . Org. Chem., Vol. 61, No. 15, 1996
Notes
δ 12.0 (d, J ) 77); 19F NMR δ -194 (d, J ) 77); EIMS 227 (M+
- 205, 9), 209 (12), 152 (32), 107 (14), 79 (16), 57 (100), 34 (8),
41 (79). Anal. Calcd for C24H46FO3P: C, 66.66; H, 10.64.
Found: C, 66.80; H, 10.74.
Further chromatography resulted in the isolation of pure (E)-
10 (0.004 g). (E)-Monoaddition product: 1H NMR δ 1.32 (m, 6H),
2.27 (dd, J ) 15, 1.6, 3H), 3.77 (s, 3H), 4.05-4.25 (m, 4H), 6.65
(dq, J ) 24, 1.6, 1H); 31P NMR δ 19.4 (s); EIMS 204 (M+ - 32,
13), 177 (25), 176 (19), 149 (42), 148 (100), 121 (21), 121 (21),
120 (13), 99 (13), 81 (29), 67 (42), 68 (17), 59 (25).
11b: 1H NMR δ 1.25-1.38 (m, 12H), 1.68 (t, J ) 16, 3H), 2.81
(dd, J ) 16, 13, 2H), 3.68 (s, 3H), 4.12-4.25 (m, 8H); 31P NMR
δ 25.6 (s); EIMS 237 (M+ - 137, 100), 205 (39), 177 (35), 149
(83), 123 (35), 109 (46), 81 (83), 65 (89). Anal. Calcd for
Eth yl 3,3-Bis(d ieth oxyp h osp h in yl)p r op a n oa te (11a ).17
To a stirred solution of diethyl phosphite (0.80 mL, 6.0 mmol)
in dry THF (12 mL) at -50 °C was added sodium bis(trimeth-
ylsilyl)amide (5.0 M, 5.0 mL, 5.0 mmol). This solution was
allowed to stir for 15 min at -50 °C after which ethyl propiolate
(0.50 mL, 5.0 mmol) was added. After 10 min the reaction
mixture was decanted into approximately 40 mL of distilled
water and extracted with Et2O (3 × 25 mL). Organic layers were
pooled and concentrated. The resulting oil was purified by dry
column chromatography (Florisil, ethyl acetate-hexane gradi-
ent) to give 11a (0.310 g, 33%) as a pale yellow oil: 1H NMR δ
1.12-1.26 (m, 15H), 2.72 (td, J ) 15.9, 6.3, 2H), 2.99 (tt, J )
24.0, 6.3, 1H), 4.01-4.14 (m, 10H); 13C NMR δ 13.4, 15.5, 15.6,
29.9 (t, J ) 5), 32.1 (t, J ) 136), 60.5, 62.1, 62.3, 170 (t, J ) 9);
31P NMR δ 22.8 (s); EIMS 273 (M+ - 101, 22), 237 (100), 189
(42), 165 (68), 135 (86), 109 (98), 91 (75), 81 (62), 65 (58). Anal.
Calcd for C13H28O8P2: C, 41.71; H, 7.54. Found: C, 41.97; H,
7.60.
Meth yl 3-(Dieth oxyp h osp h in yl)-2-bu ten oa te (10) a n d
Meth yl 3,3-Bis(d ieth oxyp h osp h in yl)bu ta n oa te (11b). To a
stirred solution of diethyl phosphite (1.6 mL, 12 mmol) in dry
THF (20 mL) at -55 °C was added sodium bis(trimethylsilyl)-
amide (1 M, 12.0 mL, 12 mmol). This was allowed to stir for 10
min, after which 9b (1.0 mL, 10 mmol) was added. After 2 h
the reaction mixture was decanted into water (65 mL). The
resulting emulsion was extracted with diethyl ether (3 × 30 mL).
The combined organic phases were dried over MgSO4, filtered,
and concentrated to give a mixture (2.14 g) of the mono- and
diphosphorylated products 10 and 11b, respectively. Column
chromatography (neutral alumina, ethyl acetate-hexane gradi-
ent) provided pure 11b (0.235 g, 11%) and a mixture (0.60 g,
28%) of (E) and (Z) monoaddition products in a 1:1 ratio.
C
13H28O8P2: C, 41.72; H, 7.54. Found: C, 41.44; H, 7.45.
Meth yl 4-(Dieth oxyp h osp h in yl)-4-flu or o-6-p h en yl-5-h ex-
yn oa te (12). To a stirred solution of sodium bis(trimethylsilyl)-
amide (1 M in THF, 1.0 mL, 1.0 mmol) in dry THF (10 mL) at
0 °C were added methyl acrylate (0.086 g, 1.0 mmol) and 3c
(0.270 g, 1.0 mmol) in rapid succession. After stirring for 2 h at
0 °C, the mixture was quenched with water (30 mL) and
extracted with Et2O (3 × 20 mL). Organic layers were pooled,
washed with a saturated NaHCO3 solution (3 × 20 mL), and
concentrated to afford essentially pure 12 (0.199 g, 56%) as an
orange oil (96% pure by 31P NMR). An analytically pure sample
was obtained by column chromatography (acidic alumina, hex-
ane-ethyl acetate 4:1): 1H NMR δ 1.35-1.45 (m, 6H), 2.55 (m,
2H), 2.75 (m, 2H), 3.71 (s, 3H), 4.25-4.43 (m, 4H), 7.30-7.55
(m, 5H); 13C NMR δ 16.4, 16.5, 28.5, 31.5, 51.8, 64.4, 64.7, 81.6
(d, J ) 25), 89.0 (t, J ) 181), 92.0, 127.6, 128.5, 129.5, 131.9,
172.8; 31P NMR δ 13.1 (d, J ) 86); 19F NMR δ -161 (d, J ) 86);
EIMS 308 (M+ - 48, 9), 269 (17), 191 (26), 159 (100), 141 (22),
81 (17). Anal. Calcd for
Found: C, 57.38; H, 6.30.
C17H22FO5P: C, 57.30; H, 6.17.
Ack n ow led gm en t. We are indebted to the National
Science Foundation (CHE9122304) and the Camille and
Henry Dreyfus Foundation for their financial support.
The authors also want to express their gratitude to the
National Science Foundation Instrument and Labora-
tory Improvement Program (DUE-9351588) and the
UMass Dartmouth Research Foundation for financing
the purchase of a high-field FT-NMR spectrometer.
(17) This compound first appeared in the literature as the product
of the alkylation of metalated methylenediphosphonate esters; only
its 31P NMR was reported. See: Quimby, O. T.; Curry, J . D.; Allan,
D.; Prentice, J . B.; Roy, C. H. J . Organomet. Chem. 1968, 13, 199-
207.
J O9602027