A highly efficient and practical synthesis of cyclic phosphinates using ring-closing metathesis

Full text of DOI:10.1021/jo981795j

J . Org. Chem. 1999, 64, 2119-2123
2119
Sch em e 1. P r ep a r a tion of Dien es 2a -2g
A High ly Efficien t a n d P r a ctica l Syn th esis
of Cyclic P h osp h in a tes Usin g Rin g-Closin g
Meta th esis
M. Bujard, V. Gouverneur,† and C. Mioskowski*
Universite´ Louis Pasteur, Laboratoire de Synthe`se
Bioorganique associe´ au CNRS, Faculte´ de Pharmacie,
74, route du Rhin-BP-24-67401 Illkirch, France
Received September 3, 1998
Structural mimics of key intermediates and transition
states have been extensively used to study and regulate
important metabolic processes. Recently, cyclic phos-
phinic acids which are nonhydrolyzable and isoteric
analogues of naturally occurring cyclic phosphodiesters
have attracted much attention as mimics of adenosine
monophosphate (cAMP), guanosine monophosphate
(cGMP), or inositol-1,2-cyclic monophosphates.1 In addi-
tion, these cyclic phosphodiesters mimics can be em-
ployed as transition states analogues for antibodies
production or as potent enzyme inhibitors.2
As part of our program aimed at synthesizing new
transition state analogues for eliciting catalytic antibod-
ies, we became interested in differently substituted cyclic
phosphinic esters. A survey of the literature revealed that
there were only a few methods for the synthesis of cyclic
phosphinates,3 and many of them suffered from either
lack of generality or low yields and used conditions that
were not compatible with the presence of various func-
tional groups. In this paper, we report a novel and highly
efficient procedure for preparing a number of diverse
cyclic phosphinates using ring-closing metathesis (RCM),
a methodology emerging as a new tool in synthetic
organic chemistry.4
Resu lts a n d Discu ssion
Su bstr a te Syn th esis. A series of symmetrical and
unsymmetrical dienes having a phosphinate moiety was
easily prepared in good yields from the corresponding
phosphinic acids. The symmetrical phosphinic acids 1a ,
1c, and 1d (Scheme 1, method A) were prepared, accord-
ing to a known procedure,5 using a one-pot intermolecular
Arbusov-type reaction between bis(trimethylsilyloxy)-
phosphine (BTSP), generated in situ from ammonium
phosphinate and hexamethyldisilazane (HMDS), and the
corresponding alkyl or allyl halide. The conversion of the
phosphinic acids 1a , 1c, and 1d into the desired phos-
phinates 2a , 2c, and 2d was achieved by esterification
with the corresponding alcohol in the presence of tri-
ethylamine, after activation of the phosphinic acids with
oxalyl chloride.6 The preparation of unsymmetrical phos-
phinic acids (Scheme 1, method B) using the sequential
addition of two different alkyl halides, as previously
described in the literature,5 proved problematic as mix-
tures of both unsymmetrical and the undesired sym-
metrical phosphinic acids were always obtained. How-
ever, these two products were easily separated by column
chromatography following esterification with the desired
alcohol to provide the analytically pure unsymmetrical
phosphinates 2e-2g. Dienes 2h and 2i were prepared
by alkylation at low temperature of the corresponding
phosphinates 2b and 2a (Scheme 2).7
* To whom correspondence should be addressed. e-mail: mioskow@
bioorga.u-strabg.fr. Phone: + 33 3 88 67 68 63. Fax: + 33 3 88 67 88
91.
† Present address: The Dyson Perrins Laboratory, University of
Oxford, South Parks Road, OX1 3QT Oxford, U.K.
(1) Montchamp, J .-L.; Frost, J . W. J . Org. Chem. 1994, 59, 7596.
Richard, J . P. J . Am. Chem. Soc. 1984, 106, 4926. Periana, R. A.; Motiu-
DeGrood, R.; Chiang, Y.; Hupe, D. J . J . Am. Chem. Soc. 1980, 102,
3923.
(2) Campbell, M. M.; Carruthers, N. I.; Mickel, S. J .; Winton, P. M.
J . Chem. Soc., Chem. Commun. 1984, 200. Gibbs, R. A.; Taylor, S.;
Benkovic, S. J . Science 1992, 258, 803. Currie, M.; Suckling, C. J .; Zhu,
L.-M.; Irvine, J .; Stimson, W. H. Tetrahedron 1995, 51, 8915.
(3) Montchamp, J .-L.; Tian, F.; Frost, J . W. J . Org. Chem. 1995,
60, 6076 and references therein.
(4) For recent synthetic applications of RCM, see: (a) Crimmins,
M. T.; King, B. W. J . Org. Chem. 1996, 61, 4192. (b) Yang, Z.; He, Y.;
Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed.
Engl. 1997, 36, 166. (c) Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P.;
Sorensen, E. J .; Danishefsky, S. J .; Zheng, Y.-H.; Chou, T.-C.; He, L.;
Horwitz, S. J . Am. Chem. Soc. 1997, 119, 2733.
(6) Froneman, M.; Modro, T. A. Synthesis 1991, 201.
(7) Liotta, L. J .; Gibbs, R. A.; Taylor, S. D.; Benkovic, P.; Benkovic,
S. J . J . Am. Chem. Soc. 1995, 117, 4729. Phillips, A. M.; Modro, T. A.
Phosphorus, Sulfur, Silicon 1991, 55, 41.
(5) Boyd, E. A.; Regan, A. C. Tetrahedron Lett. 1994, 35, 4223.
Majewski, P. Phosphorus, Sulfur, Silicon 1989, 45, 151.
10.1021/jo981795j CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/04/1999

2120 J . Org. Chem., Vol. 64, No. 6, 1999
Notes
Sch em e 2. P r ep a r a tion of Dien es 2h a n d 2i
which contains an unprotected phosphinic acid moiety
(entry 1, Table 1). However, when a solution of the
corresponding benzyl phosphinate 2a in dichloromethane9
(0.02 M) was heated at reflux in the presence of 2.5 mol
% of 3, the desired five-membered cyclic phosphinate 5a
was obtained in 80% isolated yield with no side products
detected (entry 2, Table 1).10 In addition, RCM was found
to proceed with equal efficiency with the ethyl ester
derivative 2b, affording the ethyl phosphinate 5b in an
identical yield (80%) (entry 3, Table 1). Once it had been
established that formation of a cyclic phosphinate with
3 was feasible, attention was turned toward the effect of
ring size and the olefinic substituent.
Ta ble 1. Ca ta lytic Rin g-Closin g Meta th esis of Dien es 1a
a n d 2a -2i w ith (2.5-3%) Alk ylid en e 3 (0.02 M CH2Cl2)
Under the above metathesis conditions, the formation
of both six- and seven-membered cyclic phosphinates 5e
and 5c with alkylidene 3 was completed in very high
yields and did not require extended reaction time com-
pared to the formation of the five-membered product 5a
or 5b (entries 4 and 5, Table 1).
The ring-closing metathesis can be extended to include
both R- and â-substituted phosphinate dienes, however
at the expense of reduced reactivity. Exposure of the
methyl â-substituted diene 2f to the alkylidene 3 yielded
the expected five-membered cyclic phosphinate 5f in only
50% yield (entry 6, Table 1). Similarly, alkylidene 3
showed no reaction with the phenyl-substituted diene 2g
or the â,â′-disubstituted diene 2d over 5 days, supporting
the hypothesis11 that the combination of the steric effect
of the substituent and the electron-withdrawing effect
is unfavorable for promoting ring closure (entries 7 and
8, Table 1). Moreover, the data suggested that the steric
influence on reactivity was less important for R-substi-
tuted phosphinates as exemplified with dienes 2h and
2i. Indeed, it was found that alkylidene 3 cyclized
substrates 2h and 2i into the corresponding R-substituted
heterocycles 5h and 5i in 77% and 66% yields, respec-
tively (entries 9 and 10, Table 1).
The failure of ruthenium alkylidene 3 to promote the
cyclization of the unprotected phosphinic acid 1a , the
hindered disubstituted diene 2d , and the diene 2g having
the electron-withdrawing phenyl group at the â-position
encouraged us to explore the use of the more reactive
molybdenum alkylidene 412 in an attempt to improve
reactivity. Disappointingly, under a modified RCM condi-
tion of 0.02 M in toluene at 60 °C with 6-8 mol % of
molybdenum catalyst 4, there was no significant im-
provement in the reaction profile between the two
catalysts as both afforded similar yields and reactivities
for the substrates examined (Table 2).
However, the ruthenium alkylidene 3 is a much more
convenient catalyst to use in the RCM since it does not
require rigorous purification, drying, and degassing of
substrates as seen with the more sensitive molybdenum
alkylidene 4.
a
b
Isolated yield. 100% recovered starting material.
(9) CH2Cl2 was chosen as the optimal solvent for the reactions with
3 based on lower overall conversion obtained in benzene. When the
reaction was carried out at room temperature, the RCM of substrate
2a was slower and the overall conversion of 2a into 5a after 15 h did
not go beyond 38%.
(10) The NMR analysis of the crude mixtures show only the desired
cyclized product and the starting material with no side products. No
trace of dimers was detected.
(11) Kirkland, T. A.; Grubbs, R. H. J . Org. Chem. 1997, 62, 7310.
(12) 2,6-Diisopropylphenylim id on eophylidene molybdenum(VI) bis-
(hexafluoro-tert-butoxide) was used as the catalyst: Murdzek, J . S.;
Bazan, G. C.; Robbins, J .; DiMare, M.; O′ Regan, M.; Schrock, R. R. J .
Am. Chem. Soc. 1990, 112, 3875.
RCM of P h osp h in ic Ester s. The ring-closing me-
tathesis of the acyclic dienes prepared above was achieved
using catalytic ruthenium alkylidene 3 (Cl2(PCy3)2-
RudCHPh). Table 1 summarizes the results.
Preliminary experiments showed that ruthenium alky-
8
lidene 3 was unable to catalyze the RCM of the diene 1a
(8) Schwab, P. E.; Grubbs, R. H.; Ziller, Z. W. J . Am. Chem. Soc.
1996, 118, 100.

Notes
J . Org. Chem., Vol. 64, No. 6, 1999 2121
bromide, 60 mL of toluene; yield 3.1 g (71%); pale yellow oil; 1H
NMR (CDCl3, 200 MHz) δ 6.48 (br s, 1H), 5.91-5.71 (m, 2H),
5.28-5.17 (m, 4H), 2.62 (d × d, J ) 18.1, J ) 7.8, 4H); 13C NMR
(CDCl3, 50 MHz) δ 127.6 (d, J ) 8.7), 120.5 (d, J ) 13.1), 33.9
(d, J ) 90.1); 31P NMR (CDCl3, 121.5 MHz) δ 51.6; IR (neat,
cm-1) 1638, 1232, 1160, 1058, 975, 919; MS (CI, NH3) 147 (M +
H+), 164 (M + NH4+).
Ta ble 2. Ca ta lytic Rin g-Closin g Meta th esis of Dien es 1a
a n d 2a , 2d a n d 2f w ith 6-8% Alk ylid en e 4 (0.02 M
Tolu en e)
Dibu t-3-en ylp h osp h in ic a cid (1c): 4.9 mL (23.4 mmol) of
HMDS, 0.97 g (11.7 mmol) of H2PO2- NH4+, 2.4 mL (23.4 mmol)
of 4-bromo-but-1-ene, 20 mL of toluene; yield 0.35 g (18%); pale
1
yellow oil; H NMR (CDCl3, 300 MHz) δ 5.87 (d × d × t, 2H, J
) 16.9, J ) 10.5, J ) 6.2), 5.4 (br s, 1H), 5.09 (d × d, J ) 16.9,
J ) 1.5, 2H), 5.03 (d × d, J ) 10.3, J ) 1.5, 2H), 2.37(m, 4H),
1.82(m, 4H); 13C NMR (CDCl3, 75 MHz) δ 137.3 (d, J ) 16.0),
115.3, 28.3 (d, J ) 91.5), 25.6 (d, J ) 2.9); IR (neat, cm-1) 1641,
1163, 988, 975, 913; MS (CI, NH3) 175 (M + H+).
Bis(2-m eth yla llyl)p h osp h in ic a cid (1d ): 4 mL (19 mmol)
-
of HMDS, 0.8 g (9.6 mmol) of H2PO2 NH4+, 3.9 mL (38 mmol)
of 3-bromo-2-methylpropene, 20 mL of toluene; yield 1.2 g (71%);
colorless solid (mp 75-76 °C); 1H NMR (CDCl3, 200 MHz) δ
4.99-4.87 (m, 4H), 4.43 (br s, 1H), 2.60 (4H, d, J ) 17.1 Hz),
1.91 (br s, 6H); 13C NMR (CDCl3, 50 MHz) δ 136.6 (d, J ) 10.2),
115.7 (d, J ) 11.6), 37.9 (d, J ) 88.6), 24.0; 31P NMR (CDCl3,
121.5 MHz) δ 51.2; IR(neat, cm-1) 2246, 1646, 1175, 1120, 956,
891; MS (CI, NH3) 175 (M + H+), 192 (M + NH4+).
Gen er a l P r oced u r e for P r ep a r a tion of Un sym m etr ica l
P h osp h in ic Acid s (Meth od B). A mixture of 1.2 equiv of
ammonium phosphinate and 1.2 equiv of HMDS was heated at
110 °C for 2 h. After the solution was cooled at 0 °C, CH2Cl2
was added all at once and then the less reactive alkyl halide
was introduced. The reaction was allowed to warm to room
temperature. After 12 h of stirring, the reaction was cooled at 0
°C and 1 equiv of HMDS was added at once. After stirring for 2
h at 0 °C, 1 equiv of the second alkyl halide was added at that
temperature. After stirring for another 12 h at room tempera-
ture, the mixture was filtered on Celite. The filtrate was
concentrated and the residual oil dissolved in CH2Cl2 and
washed with 4 N HCl. After concentration of the organic phase,
the residual oil was used without further purification for the
esterification.
Allylbu t-3-en ylp h osp h in ic a cid (1e): 4.2 mL (20 mmol) of
HMDS, 1.7 g (20 mmol) of H2PO2- NH4+; 2.5 g (12 mmol) of but-
3-enyl triflate; then 2.5 mL (12 mmol) of HMDS, 1.7 mL (20
mmol) of allyl bromide; yield 2.1 g of a nonseparable mixture of
1a and 1e (ratio 3/7); 1H NMR (CDCl3, 300 MHz) (deduced from
the mixture) δ 5.91-5.74 (m, 2H), 5.31-5.01 (m, 4H), 2.65 (d ×
d, J ) 17.7, J ) 7.53, 2H), 2.43-2.32 (m, 2H), 1.90-1.23 (m,
2H); 13C NMR (CDCl3, 75 MHz) (deduced from the mixture) δ
137.1 (d, J ) 14.5), 127.2 (d, J ) 10.1), 120.8 (d, J ) 13.1), 34.9
(d, J ) 88.6), 26.8 (d, J ) 93.0), 25.4 (d, J ) 4.4).
Allyl(2-m eth yla llyl)p h osp h in ic a cid (1f): 5.1 mL (24.1
mmol) of HMDS, 2.0 g (24.1 mmol) of H2PO2- NH4+; 2 mL (19.8
mmol) of 3-bromo-2-methylpropene; then 4.2 mL (19.8 mmol) of
HMDS, 1.7 mL (19.8 mmol) of allyl bromide; yield 2.0 g of a
nonseparable crude mixture of 1d and 1f (ratio 2/8); 1H NMR
(CDCl3, 200 MHz) (deduced from the mixture) δ 5.83 (m, 1H),
5.25-5.11 (m, 2H), 4.96-4.86 (m, 2H), 2.55 (d, J ) 17.5, 2H),
2.60 (d × d, 2H), 1.89 (s, 3H); 13C NMR (CDCl3, 75 MHz)
(deduced from the mixture) δ 136.9 (d), 128.3 (d, J ) 8.7), 120.0
(d, J ) 13.1), 115.4, 37.5 (d, J ) 88.6), 34.5 (d, J ) 90.1).
Allyl(2-p h en yla llyl)p h osp h in ic a cid (1g): 5.0 mL (24.0
mmol) of HMDS, 2.0 g (24.0 mmol) of H2PO2- NH4+; 0.48 g (2.4
mmol) of 1-bromo-2-phenylprop-2-ene; then 1 mL (5 mmol) of
HMDS, 4 mL (48 mmol) of allyl bromide; yield 1.4 g of a
nonseparable mixture of 1a and 1g (ratio 75/25); 1H NMR
(CDCl3, 300 MHz) (deduced from the mixture) δ 7.48-7.30 (m,
5H), 5.82 (m, 1H), 5.53 (d, J ) 4.9, 1H), 5.37 (d, J ) 4.9, 1H),
5.12 (m, 2H), 3.05 (d, J ) 17.3, 2H), 2.52 (d × d, J ) 17.7, J )
7.5, 2H).
Gen er a l P r oced u r e for P r ep a r a t ion of P h osp h in a t es
2a -2g. To a solution of 1 equiv of phosphinic acid and a catalytic
amount of DMF (2 drops) in benzene or dichloromethane at 0
°C was added dropwise 3 equiv of oxalyl chloride. After addition,
the mixture was allowed to warm to room temperature. After 1
h, the reaction was concentrated and the crude phosphinic acid
chloride was used without further purification in the next step.
To a solution of the crude phosphinic acid chloride, a catalytic
a
b
Isolated yield. 100% recovered starting material.
Con clu sion s
The efficiency of the catalytic ring-closing metathesis
combined with the ease of preparation of the dienes
makes this methodology an attractive alternative to the
formation of differently substituted five-, six-, and seven-
membered phosphinates. This is the first report related
to the metathesis of dienes including a phosphinate
function. During the course of our studies, RCM on a
phosphonate template was described in the literature.13
Further work is presently underway in our laboratory
to extend this novel strategy to the synthesis of more
functionalized and biologically active phosphorus con-
taining heterocycles.
Exp er im en ta l Section
Gen er a l Meth od s. Mass spectra were performed by A.
Valleix (CEA, Saclay) and the high-resolution mass spectra by
P. Guenot (Universite´ de Rennes I). 31P NMR spectra were
recorded using phosphoric acid (80%) as external reference.
Ammonium phosphinate14 was prepared as described in the
literature. Alkylidenes 3 and 4 were purchased from Strem. The
reactions with the air-sensitive Schrock’s catalyst were carried
out in a glovebox using dried and degassed substrates and
solvents. Although the methodology presented here relies on in
situ generation of BTSP, caution should still be exercised since
neat BTSP is highly pyrophoric.
Gen er a l P r oced u r e for P r ep a r a tion of Sym m etr ica l
P h osp h in ic Acid s (Meth od A). A solution of 1 equiv of
ammonium phosphinate, 2 equiv of HMDS, and 4 equiv of alkyl
bromide (or triflate) in toluene was refluxed overnight. After
cooling, the white precipitate (ammonium salt) was filtered over
Celite and washed with CH2Cl2. The filtrate was concentrated
and the residue treated with a 1:1 mixture of MeOH and CH2-
Cl2 for 15 min. The solution was evaporated, and the residual
oil was dissolved in CH2Cl2 and washed with 4 N HCl. After
concentration of the organic phase, the residual oil was used
without further purification in the next step. However, it could
be purified by column chromatography.
Dia llylp h osp h in ic a cid (1a ):15 12.6 mL (60 mmol) of HMDS,
2.5 g (30 mmol) of H2PO2 NH4+, 10.1 mL (120 mmol) of allyl
-
(13) Hanson, P. R.; Stoianova, D. S. Tetrahedron Lett. 1998, 39,
3939.
(14) Boyd, E. A.; J ames, K.; Regan, A. C. Tetrahedron Lett. 1992,
33, 813.
(15) Aksnes, G.; Majewski, P. Phosphorus Sulfur 1986, 26, 261.

2122 J . Org. Chem., Vol. 64, No. 6, 1999
Notes
amount of DMAP (2 mol %), and 1.1 equiv of Et3N in CH2Cl2 at
-78 °C was added dropwise 1.1 equiv of the alcohol. The mixture
was allowed to warm to room temperature. After 4 h, the mixture
was evaporated and the residue treated with pentane. After
filtration of the salts, the residue was purified by column
chromatography.
Dia llylp h osp h in ic a cid ben zyl ester (2a ): 2 g (13.5 mmol)
of 1a , 3.5 mL (40.5 mmol) of (COCl)2; 2.1 mL (14.9 mmol) of
Et3N, 1.55 mL (14.9 mmol) of benzylic alcohol; column chroma-
tography (ether); yield 1.8 g (55%); Rf ) 0.3 (ether); pale yellow
oil; 1H NMR(CDCl3, 200 MHz) δ 7.41-7.38 (m, 5H), 5.82 (m,
2H), 5.26-5.14 (m, 4H), 5.08 (d, J ) 7.8, 2H), 2.64 (d × d, J )
17.4, J ) 7.5, 4H); 13C NMR (CDCl3, 75 MHz) δ 136.6 (d, J )
5.8), 128.6, 128.4, 127.9, 127.5 (d, J ) 8.7), 120.6(d, J ) 13.1),
66.1 (d, J ) 7.3), 33.8 (d, J ) 88.6); 31P NMR (CDCl3, 121.5 MHz)
δ +50.7; IR (neat, cm-1) 1636, 1245, 1187, 1036, 1001; HRMS
calcd for C13H17O2P (M+•) 236.0966, found 236.0963.
Dia llylp h osp h in ic a cid eth yl ester (2b):16 1.5 g (10.3
mmol) of 1a , 1.8 mL (20.6 mmol) of (COCl)2; 1.7 mL (12.4 mmol)
of Et3N, 0.73 mL (12.4 mmol) of ethanol; column chromatography
(hexane/AcOEt:60/40); yield 0.92 g (51%); Rf ) 0.23 (AcOEt); pale
yellow oil; 1H NMR (CDCl3, 300 MHz) δ 5.9-5.74 (m, 2H), 5.26-
5.18 (m, 4H), 4.11 (d × q, J ) 7.5, J ) 7.2, 2H), 2.63 (d × d, J
) 17.3, J ) 7.5, 4H), 1.33 (t, J ) 7.2, 3H); 13C NMR (CDCl3, 50
MHz) δ 127.6 (d, J ) 8.7), 120.3 (d, J ) 13.1), 60.7 (d, J ) 5.8),
33.6 (d, J ) 88.6), 16.6 (d, J ) 5.8); 31P NMR (CDCl3, 121.5 MHz)
δ +49.4; IR (neat, cm-1) 1637, 1246, 1186, 1037; HRMS calcd
for C8H15O2P (M+•) 174.0810, found 174.0813.
MHz) δ 7.36 (m, 5H), 5.8 (m, 1H), 5.22 (d × d, 1H, J ) 6.1, J )
3.1), 5.19 (d × d, 1H, J ) 16.1, J ) 3.0), 5.08 (d, J ) 7.5, 2H),
4.97 (d, J ) 4.0, 1H), 4.87 (d, J ) 4.0, 1H), 2.65 (d × d, J ) 17.0,
J ) 7.5), 2.61 (d, J ) 17.3), 1.90 (s, 3H); 13C NMR (CDCl3, 50
MHz) δ136.7, 136.5(d), 128.6, 128.3, 127.8, 127.7, 120.4 (d, J )
13.1), 115.9 (d, J ) 11.6), 66.1 (d, J ) 7.3), 37.6 (d, J ) 87.2),
34.0 (d, J ) 88.6), 24.0; 31P NMR (CDCl3, 121.5 MHz) δ +51.1;
IR (neat, cm-1) 1636, 1242, 1214, 1036, 1000, 918; HRMS calcd
for C14H19O2P (M+•) 250.1123, found 250.1115.
Allyl(2-p h en yla llyl)p h osp h in ic a cid ben zyl ester (2g):
1.4 g of a mixture of both phosphinic acids 1a and 1g (75:25)
was used; 2.2 mL (40 mmol) of (COCl)2, 20 mL of benzene; 2.5
mL (15 mmol) of Et3N, 1.9 mL (15 mmol) of benzylic alcohol;
+
column chromatography (ether); yield of 2g from H2PO2- NH4
0.44 g (58%); Rf ) 0.3 (ether); colorless oil; 1H NMR(CDCl3, 300
MHz) δ 7.47-7.20 (m, 10H), 5.8 (m, 1H), 5.74 (m, 1H), 5.52 (d,
J ) 4.9, 1H), 5.34 (d, J ) 4.2, 1H), 5.17 (m, 1H), 5.07 (m, 1H),
5.02 (d × d, J ) 11.6, J ) 10.8, 1H), 4.85 (d × d, J ) 11.7, J )
9.0, 1H), 3.11 (d, J ) 15.8, 2H), 2.56 (d × d, J ) 17.0, J ) 7.5,
2H); 13C NMR (CDCl3, 75 MHz) δ 140.7, 138.9 (d, J ) 8.7), 136.6
(d, J ) 5.8), 128.5, 128.2, 127.9, 127.8, 127.5 (d, J ) 8.7), 126.4,
120.5 (d, J ) 13.1), 117.8 (d, J ) 10.2), 66.1 (d, J ) 7.3), 35.4 (d,
J ) 71.2), 34.3 (d, J ) 74.1); 31P NMR (CDCl3, 121.5 MHz) δ
+50.32; IR (neat, cm-1) 1245, 1010, 920, 840-701; HRMS calcd
for C19H21O2P (M+•) 312.1279, found 312.1280.
Allyl-l(1-m eth yla llyl)p h osp h in ic Acid Ben zyl Ester (2h ).
To a solution of 0.3 g (1.27 mmol) of 2a and 0.96 mL (6.35 mmol)
of TMEDA in 1.6 mL of THF at -78 °C was added dropwise 1.4
mmol of LDA (0.85 M). After stirring for 5 min, 0.12 mL (1.9
mmol) of iodomethane was added slowly at -78 °C. After stirring
for 15 min, the reaction mixture was quenched with EtOH/H2O
(2/1) at -78 °C. The mixture was treated with saturated NH4Cl
and extracted with AcOEt. After the usual workup, compound
2h was purified by column chromatography (hexane/EtOAc 4/6);
yield 0.19 g (60%); Rf ) 0.53 (AcOEt); colorless oil; mixture of
two diastereomers (75:25) (minor diastereomer is indicated with
Bis(bu t-3-en yl)p h osp h in ic a cid ben zyl ester (2c): 0.28
g (1.6 mmol) of 1c, 0.42 mL (4.8 mmol) of (COCl)2, 5 mL of
benzene; 0.25 mL (1.8 mmol) of Et3N, 0.19 mL (1.8 mmol) of
benzylic alcohol; column chromatography (ether); yield 0.23 g
1
(55%); Rf ) 0.28 (ether); yellow oil; H NMR (CDCl3, 300 MHz)
δ 7.40-7.34 (m, 5H), 5.82 (d × d × t, J ) 17.0, J ) 10.2, J )
6.4, 2H), 5.08-4.99 (m, 4H), 5.05 (d, 2H, J ) 7.9), 2.38-2.28
(m, 4H), 1.94-1.75 (m, 4H); 13C NMR (CDCl3, 50 MHz) δ 137.1
(d, J ) 16.0), 136.8 (d, J ) 5.8), 128.6, 128.3, 127.8, 115.3, 65.6
(d, J ) 5.8), 27.7 (d, J ) 88.6), 25.9 (d, J ) 2.9); 31P NMR (CDCl3,
121.5 MHz) δ +57.7; IR (neat, cm-1) 1640, 1232, 1197, 1000,
915; HRMS calcd for C15H21O2P (M+•) 264.1279, found 264.1278.
Bis(2-m eth yla llyl)p h osp h in ic a cid ben zyl ester (2d ): 1
g (5.7 mmol) of 1d , 1.5 mL (17.1 mmol) of (COCl)2, 10 mL of
CH2Cl2; 0.65 mL (6.3 mmol) of Et3N, 0.88 mL (6.3 mmol) of
benzylic alcohol; column chromatography (ether); yield 0.75 g
(70%); Rf ) 0.35 (ether); colorless oil; 1H NMR (CDCl3, 300 MHz)
δ 7.4-7.32 (m, 5H), 5.09 (d, J ) 7.3, 2H), 4.97 (d, J ) 4.0, 2H),
4.88 (d, J ) 4.0, 2H), 2.64 (d, J ) 16.8, 4H), 1.9 (s, 6H); 13C
NMR (CDCl3, 75 MHz) δ 136.8, 136.6 (d, J ) 8.7), 128.5, 128.3,
127.9, 115.8 (d, J ) 11.6), 66.2 (d, J ) 5.8), 38.0 (d, J ) 85.7),
24.1; 31P NMR (CDCl3, 121.5 MHz) δ +51.0; IR (neat, cm-1) 1645,
1228, 1195, 1009, 892; HRMS calcd for C15H21O2P (M+•) 264.1279,
found 264.1278.
1
*) H NMR (CDCl3, 300 MHz) δ 7.37-7.29 (m, 5H), 5.99-5.75
(m, 1H), 5.24-5.14 (m, 4H), 5.02 (d, J ) 7.9, 2H), 2.78-2.59 (m,
3H), 1.32 (d × d, J ) 16.6, J ) 7.0, 3H) (1.30*(d × d, J ) 16.9,
J ) 7.2)); 13C NMR (CDCl3, 75 MHz) δ 136.9 (d, J ) 5.8) (136.8
*(d, J ) 4.3)), 134.7 (d, J ) 7.3) (134.4* (d, J ) 7.3)), 128.6, 128.3,
128.2, 127.8, 127.7, 127.6, 127.5, 120.3 (d, J ) 13.1), 117.93 (d,
J ) 11.6) (117.89* (d, J ) 11.6)), 66.3 (d, J ) 7.3) (65.5*(d, J )
5.8)), 38.5 (d, J ) 88.6) (38.3* (d, J ) 88.6)), 32.4 (d, J ) 84.3)
(32.4* (d, J ) 84.3)), 12.5 (d, J ) 4.3) (12.3* (d, J ) 4.3)); 31P
NMR (CDCl3, 121.5 MHz) δ +53.4; IR (neat, cm-1) 1242, 1214,
1036, 1000, 918; HRMS calcd for C14H19O2P (M+•) 250.1123,
found 250.1115.
Allyl(1-b en zyla llyl)p h osp h in ic Acid E t h yl E st er (2i).
Compound 2i was prepared in a manner similar to that of 2h
using 0.2 g (1.15 mmol) of 2b, 0.87 mL (5.7 mmol) of TMEDA,
1.3 mmol of LDA (0.85 M), 1.5 mL of THF, and 0.2 mL (1.7 mmol)
of benzyl bromide. Compound 2i was purified by column chro-
matography (hexane/EtOAc 3/7); yield 0.1 g (35%); Rf ) 0.33
(AcOEt); colorless oil; mixture of two diastereomers (70:30)
Allylbu t-3-en ylp h osp h in ic a cid ben zyl ester (2e): 2 g of
a mixture of both phosphinic acids 1a and 1e (30:70) was used;
3.9 mL (45 mmol) of (COCl)2, 25 mL of benzene; 3.2 mL (23
mmol) of Et3N, 2.4 mL (23 mmol) of benzylic alcohol; column
1
(minor diastereomer is indicated with *) H NMR (CDCl3, 300
MHz) δ 7.28-7.13 (m, 5H), 5.98-5.60 (m, 2H), 5.28-4.91 (m,
4H), 4.16 (d × t, J ) 7.3, 2H) (4.14* (d × t, J ) 7.3, 2H), 3.37-
3.17 (m, 1H), 2.93-2.58 (m, 4H), 1.34 (t, J ) 7.3, 3H) (1.33* (t,
J ) 7.3, 3H)); 13C NMR (CDCl3, 75 MHz) δ 138.9 (d, J ) 14.5),
133.0 (d, J ) 8.7) (132.5* (d, J ) 5.8)), 129.07 (129.01*), 128.2,
127.7 (d, J ) 8.7)126.3, 120.6, 120.4, 120.3, 120.2, 120.1, 120.0,
61.1 (d, J ) 7.3) (60.69* (d, J ) 7.3)), 46.5 (d, J ) 88.6) (46.1*
(d, J ) 90.1)), 33.1, 33.0, 32.8 (d, J ) 87.2) (32.7* (d, J ) 85.7),
16.7 (d, J ) 5.8); 31P NMR (CDCl3, 121.5 MHz) δ +50.79
(+50.88*); IR (neat, cm-1) 1636, 1236, 1199, 1037, 952, 918-
700; HRMS calcd for C15H21O2P (M+•) 264.1279, found 264.1278.
Gen er al P r ocedu r e of Rin g-Closin g Metath esis of Dien es
2a -2h Usin g Alk ylid en e 3. To a solution of the diene in dry
CH2Cl2 was added catalyst 3. The reaction mixture was refluxed,
and the disappearance of the starting material was monitored
by TLC. The reaction was concentrated and purified on silica
gel.
-
chromatography (hexane/EtOAc 1/1); yield of 2e from H2PO2
NH4 1.6 g (60%); Rf ) 0.54 (AcOEt); colorless oil; 1H NMR
+
(CDCl3, 300 MHz) δ 7.40-7.36 (m, 5H), 5.82 (m, 2H), 5.23-5.16
(m, 2H), 5.09-4.99 (m, 4H), 2.63 (d × d, J ) 17.2, J ) 7.7, 2H),
2.34 (m, 2H), 1.85 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 137.1
(d, J ) 16.0), 136.7 (d, J ) 5.8), 128.6, 128.4, 127.9, 127.8, 127.7
(d, J ) 8.7), 120.3 (d, J ) 13.1), 115.3, 65.9 (d, J ) 5.8), 34.8 (d,
J ) 85.7), 26.9 (d, J ) 91.6), 25.7 (d, J ) 2.9); 31P NMR (CDCl3,
121.5 MHz) δ +54.3; IR (neat, cm-1) 1638, 1242, 1214, 1189,
1036, 1008, 919; HRMS calcd for C14H19O2P (M+•) 250.1123,
found 250.1115.
Allyl(2-m eth yla llyl)p h osp h in ic a cid ben zyl ester (2f): 2.0
g of a mixture of both phosphinic acids 1f and 1d (20:80) was
used; 3.5 mL (40 mmol) of (COCl)2, 25 mL of CH2Cl2; 2.8 mL
(19.8 mmol) of Et3N, 2.0 mL (19.8 mmol) of benzylic alcohol;
-
+
column chromatography (ether); yield of 2f from H2PO2 NH4
0.8 g (17%); Rf ) 0.4 (ether); colorless oil; 1H NMR (CDCl3, 200
Gen er al P r ocedu r e of Rin g-Closin g Metath esis of Dien es
2a -2h Usin g Alk ylid en e 4. To a solution of catalyst 4 in dry
degassed benzene was added a solution of the diene in dry
degassed benzene. After stirring at 60 °C until disappearance
(16) Lutsenko, I. F.; Prischenko, A. A.; Livantsov, M. V. Phosphorus
Sulfur 1988, 35, 329.

Notes
J . Org. Chem., Vol. 64, No. 6, 1999 2123
of the starting material, the reaction was concentrated and
purified on silica gel.
3: 0.075 g (0.3 mmol) of 2a , 0.012 g (2%) of 3, 15 mL of CH2Cl2,
4 h; column chromatography (ether); yield 0.033 g (50%). With
4: 0.1 g (0.4 mmol), 0.02 g (6.5%) of 4, 20 mL toluene, yield 0.044
g (50%); yellow oil; 1H NMR (CDCl3, 300 MHz) δ 7.40-7.36 (m,
5H), 5.52 (d, J ) 34.7, 1H), 5.10 (d, J ) 9.0, 2H), 2.57-2.24 (m,
4H), 1.78 (s, 3H); 13C NMR (CDCl3, 75.5 MHz) δ 136.5, 136.4,
136.2, 128.7, 128.5, 127.9 120.4 (d, J ) 11.6), 66.3 (d, J ) 7.3),
33.7 (d, J ) 91.5), 31.1 (d, J ) 87.2), 20.8 (d, J ) 13.1); 31P NMR
(CDCl3, 121.5 MHz) δ +76.1; IR (neat, cm-1) 1295, 1236, 1189,
1033, 1002; HRMS calcd for C12H15O2P (M+•) 222.0810, found
222.0802.
1-Ben zyloxy-3-p h osp h olen e 1-Oxid e (5a ).17 With 3: 2.1 g
(8.9 mmol) of 2a , 0.15 g (2%) of 3, 300 mL of CH2Cl2, 2 h; column
chromatography (hexane/EtOAc 2/8); yield 1.5 g (80%). With 4:
0.1 g (0.42 mmol), 0.025 g (8%) of 4, 20 mL of toluene, yield 0.083
g (95%); Rf ) 0.27 (AcOEt/hexane 80/20); pale yellow oil; 1H NMR
(CDCl3, 300 MHz) δ 7.42-7.33 (m, 5H), 5.91 (d, J ) 33.5, 2H),
5.12 (d, J ) 8.6, 2H), 2.52-2.32 (m, 4H); 13C NMR (CDCl3, 75
MHz) δ 136.2 (d, J ) 5.8), 128.6, 128.5, 127.9, 126.9 (d, J ) 16.0),
66.3 (d, J ) 7.3), 29.4 (d, J ) 90.1); 31P NMR (CDCl3, 121.5 MHz)
δ +75.7; IR (neat, cm-1) 1251, 1204, 1008, 660; HRMS calcd for
1-Ben zyloxy-2-m eth yl-3-p h osp h olen e 1-oxid e (5h ): 0.1 g
(0.4 mmol) of 2h , 0.011 g (3%) of 3, 20 mL of CH2Cl2, 3.5 h;
column chromatography (hexane/EtOAc 3/7); yield 0.068 g (77%)
of two diastereomers; ratio 29/71. Minor diastereomer: 22 mg;
Rf ) 0.47 (AcOEt); colorless oil; 1H NMR (CDCl3, 300 MHz) δ
7.40-7.35 (m, 5H), 5.86 (d, J ) 32.4, 2H), 5.10 (d, J ) 8.7, 2H),
2.51-2.31 (m, 3H), 1.25 (d × d, J ) 16.6, J ) 7.5, 3H); 13C NMR
(CDCl3, 50 MHz) δ 136.4 (d, J ) 5.8), 134.5 (d, J ) 20.3), 128.6,
128.5, 127.9, 124.9 (d, J ) 16.0), 66.3 (d, J ) 7.3), 33.7 (J )
91.5), 29.0 (J ) 88.6), 13.6; 31P NMR (CDCl3, 121.5 MHz) δ 75.8.
C
11H13O2P (M+•) 208.0653, found 208.0643.
1-E t h oxy-3-p h osp h olen e 1-Oxid e (5b ).18 With 3: 0.15 g
(0.86 mmol) of 2b, 0.014 g (2%) of 3, 40 mL of CH2Cl2, 2 h;
column chromatography (hexane/EtOAc 1/9); yield 0.1 g (80%);
1
Rf ) 0.33 (AcOEt/hexane 90/10); colorless oil; H NMR (CDCl3,
300 MHz) δ 5.92 (d, J ) 33.2, 2H), 4.13 (d × q, J ) 7.5, J ) 7.2,
2H), 2.44 (d, J ) 11.7, 4H), 1.37 (t, J ) 7.1, 3H); 13C NMR
(CDCl3, 75 MHz) δ 127.0 (d, J ) 16.0), 60.9 (d, J ) 5.8), 29.3 (d,
J ) 91.7), 16.6 (d, J ) 7.3); 31P NMR (CDCl3, 121.5 MHz) δ
+74.5; IR (neat, cm-1) 2924, 1250, 1201, 1034, 960, 660; HRMS
calcd for C6H11O2P (M+•) 146.0497, found 146.0494.
1
Major diastereomer: 48 mg; Rf ) 0.4 (AcOEt); colorless oil; H
NMR (CDCl3, 300 MHz) δ 7.40-7.36 (m, 5H), 5.91-5.73 (m, 2H),
5.15 (m, 2H), 2.74 (m, 1H), 2.50-2.29 (m, 2H), 1.22 (d × d, J )
15.8, J ) 7.2, 3H); 13C NMR (CDCl3, 50 MHz) δ 136.5 (d, J )
5.8), 134.5 (d, J ) 18.9), 128.6, 128.3, 127.7, 124.7 (d, J ) 14.5),
66.2 (d, J ) 7.3), 35.4 (d, J ) 93.0), 29.5 (d, J ) 85.7), 12.8 (d,
1-Ben zyloxy-2,3,6,7-tetr ah ydr oph osph epin e 1-Oxide (5c).
With 3: 0.075 g (0.28 mmol) of 2c, 0.006 g (2.5%) of 3, 15 mL of
CH2Cl2, 1.5 h; column chromatography (EtOAc); yield 0.064 g
1
(97%); Rf ) 0.26 (AcOEt); pale yellow oil; H NMR (CDCl3, 300
J ) 5.8); 31P NMR (CDCl3, 121.5 MHz) δ +75.72; IR (neat, cm-1
1456, 1250, 1195, 1036, 1009; HRMS calcd for C12H15O2P (M+•
222.0810, found 222.0823.
)
)
MHz) δ 7.43-7.33 (m, 5H), 5.89 (m, 2H), 5.08 (d, J ) 7.9, 2H),
2.33-2.23 (m, 4H), 1.96-1.72 (m, 4H); 13C NMR (CDCl3, 50
MHz) δ 136.8 (d, J ) 5.8), 131.8, 128.6, 128.4, 127.9, 65.2 (d, J
) 5.8), 28.5 (d, J ) 87.2), 19.5 (d, J ) 4.3); 31P NMR (CDCl3,
121.5 MHz) δ +59.1; IR (neat, cm-1) 1210, 1171, 1042, 1018,
1000, 961; HRMS calcd for C13H17O2P (M+•) 236.0966, found
236.0963.
2-Ben zyl-1-eth oxy-3-p h osp h olen e 1-oxid e (5i): 0.06 g (0.23
mmol) of 2i, 7 mg (3%) of 3; 12 mL of CH2Cl2, 2 h; column
chromatography (EtOAc); yield 0.035 g (66%); colorless oil; Rf
) 0.37 (AcOEt); 1H NMR (CDCl3, 300 MHz) δ 7.38-7.21 (m, 5H),
5.97-5.68 (m, 2H), 4.15 (m, 2H), 3.14 (m, 1H), 2.94 (m, 1H), 2.57
(m, 3H), 1.37 (t, J ) 7.2, 3H); 13C NMR (CDCl3, 75.5 MHz) δ
139.2 (d, J ) 11.6), 132.2 (d, J ) 20.3), 128.7, 128.5, 126.4, 125.3
(d, J ) 13.1), 61.2 (d, J ) 5.8), 42.2 (d, J ) 91.5), 34.3 (d, J )
4.4), 29.9 (d, J ) 85.7), 16.6 (d, J ) 5.8); 31P NMR (CDCl3, 121.5
MHz) δ +72.59; IR (neat, cm-1) 1245, 1035, 960; HRMS calcd
for C13H17O2P (M+•) 236.0966, found 236.0963.
1-Ben zyloxy-5,6-dih ydr o-2H ph osph or in an e 1-Oxide (5e).
With 3: 0.15 g (0.6 mmol) of 2e, 0.01 g (2.0%) of 3, 30 mL of
CH2Cl2, 30 min; column chromatography (EtOAc); yield 0.128 g
1
(96%); Rf ) 0.14 (AcOEt); pale yellow oil; H NMR (CDCl3, 300
MHz) δ 7.39-7.33 (m, 5H), 5.88-5.55 (m, 2H), 5.09 (d, J ) 8.7,
2H), 2.54-2.37 (m, 4H), 1.90 (m, 2H); 13C NMR (CDCl3, 75 MHz)
δ 136.7 (d, J ) 5.8), 128.6, 128.3, 128.2 (d, J ) 17.4), 127.8, 121.3
(d, J ) 5.8), 65.5 (d, J ) 5.8), 26.3 (d, J ) 88.6), 24.5 (d, J )
5.8), 23.4 (d, J ) 87.2); 31P NMR (CDCl3, 121.5 MHz) δ +48.1;
IR (neat, cm-1) 1680, 1290, 1230, 1193, 1040, 1009, 821; HRMS
calcd for C12H15O2P (M+•) 222.0810, found 222.0823.
Ackn owledgm en t. We gratefully acknowledge Rous-
sel-Uclaf and the Centre National de la Recherche
Scientifique for generous financial support to M.B.,
Professor J ohn Osborn for helpful discussions, and A.
Valleix and P. Guenot for running the mass spectra.
1-Ben zyloxy-3-m eth yl-3-p h osp h olen e 1-Oxid e (5f).19 With
(17) Liotta, L. J .; Gibbs, R. A.; Taylor, S. D.; Benkovic, P. A.;
Benkovic, S. J . J . Am. Chem. Soc. 1995, 117, 4729. Currie, M.;
Suckling, C. J .; Zhu, L.-M.; Irvine, J .; Stimson, N. Tetrahedron 1995,
32, 8915.
(18) Hunger, K.; Hasserodt, U.; Korte, F. Tetrahedron 1964, 1593.
(19) Vizel, A. O. Dokl. Chem. (Engl. Transl) 1965, 160, 120.
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and 31P
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O981795J