Copper-mediated displacements of allylic THP ethers on a bisphosphonate template

Article abstract of DOI:10.1016/j.jorganchem.2004.10.013

The copper-mediated displacement of allylic THP ethers by Grignard reagents has been examined in a system that contains a geminal bisphosphonate ester. With Grignard reagents derived from several aromatic halides or benzyl bromide the displacement proceed

Full text of DOI:10.1016/j.jorganchem.2004.10.013

Journal of Organometallic Chemistry 690 (2005) 2521–2530
www.elsevier.com/locate/jorganchem
Copper-mediated displacements of allylic THP ethers on a
bisphosphonate template
*
Larry W. Shull, David F. Wiemer
Department of Chemistry, University of Iowa, 305 CB, Iowa City, IA 52242-1294, USA
Received 27 June 2004; accepted 6 October 2004
Available online 19 November 2004
Abstract
The copper-mediated displacement of allylic THP ethers by Grignard reagents has been examined in a system that contains a
geminal bisphosphonate ester. With Grignard reagents derived from several aromatic halides or benzyl bromide the displacement
proceeds in attractive yields, but more mixed results were obtained from reactions with alkyl halides. In addition to its role as a
nucleophile, the Grignard reagent also appears to deprotonate the bisphosphonate to generate an anionic intermediate. Formation
of this anion appears to limit competitive nucleophilic attack at the phosphonate group and provides an intermediate that can be
trapped by reaction with an electrophilic reagent such as methyl iodide to access a more substituted system.
Ó 2004 Elsevier B.V. All rights reserved.
Keywords: Bisphosphonate; Phosphonate; Grignard reagent; Displacement; THP ether
1. Introduction
dialkyl phosphite to an acyl phosphonate [6], and very
recently through treatment of a carbonyl compound
with an excess of strong base and diethyl phosphoro-
chloridite followed by oxidation with hydrogen peroxide
[7]. Structure–activity studies on geminal bisphospho-
nates have indicated that their activity is highly depend-
ent upon the non-phosphorus substituents of the central
carbon [8], but many of these synthetic methods involve
carbon–phosphorus bond formation which can require
that structural diversity be incorporated early in the syn-
thetic sequence. Synthetic strategies that can be used to
elaborate a carbon skeleton in the presence of the bis-
phosphonate motif might offer more efficient access to
a variety of structures from a common intermediate.
Recently, we have reported a copper-mediated dis-
placement of allylic tetrahydropyranyl (THP) ethers by
various Grignard reagents [9]. While the THP ether is
generally viewed as stable to Grignard reactions [10],
displacement occurs readily in simple allylic systems
upon exposure to Grignard reagents in the presence of
Cu(I). Application of this reaction to substrates that
The structural similarity of geminal bisphosphonic
acids (1) to inorganic pyrophosphate (2) is widely recog-
nized, and this relationship has served as the inspiration
for synthesis of many derivatives of the parent methyl-
enebisphosphonate. Several substituted bisphospho-
nates have clinical applications (Fig. 1), especially in
treatment of bone diseases such as osteoporosis, Pagetꢀs
disease of the bone, myeloma, and bone metastases [1].
As a result, a number of methods have been developed
for their synthesis, including reaction of a carboxylic
acid with phosphorous acid and phosphorus trichloride
[2], by alkylation of tetraalkyl methylenebisphosphonate
[3], by reaction of lactams or amides with trialkylphos-
phites [4], by Michael-type addition to ethylidene bis-
phosphonate esters [5], by nucleophilic addition of a
*
Corresponding author. Tel.: +1 319 335 1365; fax: +1 319 335
1270.
E-mail address: david-wiemer@uiowa.edu (D.F. Wiemer).
0022-328X/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.10.013

2522
L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
hydroxylation of linear isoprenoids by reaction with
selenium dioxide in the presence of 4-hydroxybenzoic
acid (HBA) affords E-specific hydroxylation of the ter-
minal prenyl unit [14]. When the bisphosphonate 4
was treated with selenium dioxide, a mixture of the ally-
lic alcohol and the corresponding aldehyde resulted.
This mixture, after work-up and concentration, was
treated with sodium borohydride to afford the alcohol
5. The reaction sequence allowed installation of an hyd-
roxyl group at the E terminal position but, despite
numerous attempts to optimize the reaction conditions,
only modest yields were obtained. Reaction of the alco-
hol 5 with dihydropyran (DHP) under standard condi-
tions gave the desired allylic THP ether 6 in good
yield. A parallel series of reactions was used to prepare
the tetramethyl ester 9 from tetramethyl methylenebis-
phosphonate. Yields for the later steps in this sequence
closely matched those for the tetraethyl series, but the
initial alkylation only proceeds in modest yield perhaps
because the diminished steric hindrance of the methyl
esters allows more facile dialkylation.
To test the viability of the THP displacement in the
presence of a bisphosphonate, the ether 6 was treated
with an excess of commercial phenylmagnesium bro-
mide (10a, ꢀ10 eq) in the presence of copper iodide
(1.5 eq). Displacement took place in high yield to afford
the bisphosphonate 11a with no evidence of attack at
phosphorus based on TLC analysis. Several other aro-
matic Grignard reagents were examined, including the
m-tolyl, m-trifluoromethylphenyl, m-methoxyphenyl,
and p-biphenyl reagents (10b–e, respectively). In each
case, the displacement proceeded smoothly to afford
the substituted bisphosphonates 11b–e. Results were
more mixed with the Grignard reagents derived from
alkyl bromides. Benzyl magnesium bromide (10f)
O
P
O
P
O
P
O
P
HO
HO
OH
OH
HO
HO
OH
OH
O
R
R'
1
2
-bisphosphonic acid)
(pyrophosphoric acid)
R = OH, R' = CH3 (etidronate)
R = R' = Cl (clodronate)
R = OH, R' = CH2CH2NH2 (pamidronate)
R = OH, R' = (CH2)3NH2 (alendronate)
R = OH, R' = CH2(m-C5H4N) (risedronate)
Fig. 1. General structure of an a,a-bisphosphonic acid (1) and some
clinically useful examples.
include a bisphosphonate motif might be limited by
Grignard attack at phosphorus itself or at the alkyl
groups esterified to phosphorus [11]. However, some
organometallic reagents add to the carbonyl group of
b-keto phosphonates without significant attack at the
phosphorus or its esters [12], and so this strategy
appeared to be worthy of further exploration. In this pa-
per, we report an investigation into the copper-mediated
displacement of allylic THP ethers in the presence of the
bisphosphonate functionality.
2. Results and discussion
Synthesis of the first substrates for this reaction pro-
ceeded as shown in Scheme 1. Commercially available
geranyl bromide (3) was allowed to react with the anion
of tetraethyl methylenebisphosphonate to afford the ger-
anylated 1,1-bisphosphonate ester 4 along with a small
amount of the dialkyl bisphosphonate [13]. Allylic
O
O
(RO)2P
P(OR)2
O
P(OR)2
Br
NaH, 15-C-5
(RO)2P
3
O
4 R = CH2CH3 (90%)
7 R = CH3 (43%)
1) SeO2, tBuOOH, HBA
2) NaBH4
O
DHP
pTsOH
O
P(OR)2
P(OR)2
(RO)2P
(RO)2P
O
THPO
HO
O
6 R = CH2CH3 (96%)
9 R = CH3 (93%)
5 R = CH2CH3 (48%)
8 R = CH3 (54%)
Scheme 1. Synthesis of allylic THP ethers incorporating a bisphosphonate moiety.

L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
2523
reacted smoothly to afford the expected bisphosphonate
11f in 75% yield. Under the same reaction conditions,
the Grignard reagents derived from isoamyl bromide
(10g) or citronellyl bromide (10h) reacted in more mod-
erate yields (57% and 34%, respectively), and no prod-
ucts were obtained from attempted reactions with
1-bromo-3-methyl-2-butene (10i). This could be a result
of lower stability of the organometallic intermediates de-
rived from these alkyl bromides or from their dimeriza-
tion under the reaction conditions (Scheme 2).
Reaction of the tetramethyl ester 9 with phenylmag-
nesium bromide (10a) also was examined (Scheme 3).
In this case, the desired displacement was observed,
but the yield was significantly lower than that observed
with the tetraethyl ester 6 under parallel reaction condi-
tions (54% vs 86%). The 31P NMR spectrum of the reac-
tion mixture did not reveal the presence of products
resulting from attack at phosphorus (i.e., a phosphinate
or phosphine oxide), but it is possible that Grignard at-
tack at the methyl groups results in formation of toluene
[11].
To gain access to more substituted bisphosphonates,
and to secure more information about the processes in-
volved in this reaction, the bisphosphonate 6 was treated
with base and methyl iodide to obtain the methylated
product 13 (Scheme 4). When bisphosphonate 13 was
treated with phenylmagnesium bromide (10a), the de-
sired bisphosphonate 14 was not observed. Instead, a
complex mixture of polar products was obtained. The
dialkyl bisphosphonate 14 could be obtained from com-
pound 6 through a modified reaction sequence where
displacement precedes alkylation. Because an excess of
the Grignard reagent is employed in the THP displace-
ments, it is likely that some is quenched through
abstraction of a proton from the a position of the bis-
phosphonate. Generation of an intermediate bisphos-
phonate anion may limit attack at phosphorus itself or
at the phosphonate esters while allowing a THP dis-
placement at the remote allylic carbon. If this is the case,
then the initial product of the displacement would be the
anion 15, and this anion might be available for further
reaction. In the experiment, after treatment of bisphos-
phonate 6 with excess phenyl magnesium bromide, addi-
tion of methyl iodide prior to an acidic work-up did
result in methylation and after work-up gave approxi-
mately a 1:1 mixture of the methylated product 14 and
compound 11a. While this mixture was difficult to sepa-
rate, treatment with additional base and methyl iodide
resulted in complete conversion to the desired product,
compound 14. These experiments do support the view
that a bisphosphonate anion is formed during this reac-
tion sequence, but also suggest that better yields of a
dialkyl bisphosphonate might be obtained through a
two-step procedure.
If the reaction sequence from the THP ether 6 to the
substitution products 11a–i does involve formation of
an intermediate bisphosphonate-stabilized anion, the
significant base strength of a typical Grignard reagent
suggests that this process might be applicable in sys-
tems less acidic than a bisphosphonate. To begin explo-
ration of this concept, the monophosphonate 16 was
prepared (Scheme 5) by alkylation of an anion derived
from diethyl methylphosphonate with geranyl bromide
(3). Oxidation of phosphonate 16 with SeO2 and
tBuOOH, followed by reduction of the resulting mix-
ture of aldehyde and alcohol with NaBH4, gave the de-
sired alcohol 17 in modest yield. After conversion of
alcohol 17 to the THP ether 18, treatment with
O
RMgBr
10a-i
O
P(OEt)2
P(OEt)2
CuI
(EtO)2P
(EtO)2P
THPO
R
O
O
6
11a-i
(86%)
R = a:
d:
g:
(57%)
(60%)
OCH3
(77%)
CH3
(70%)
CF3
b:
c:
C6H5
(90%)
e:
f:
h:
(34%)
(--)
(75%)
i:
Scheme 2. Cu-mediated displacements of allylic THP ethers.

2524
L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
O
O
C6H5MgBr
P(OMe)2
P(OMe)2
CuI
54%
(MeO)2P
C6H5
(MeO)2P
THPO
O
O
9
12
Scheme 3. Cu-mediated displacement of an allylic THP ether.
MeI
NaH
O
O
15-Cr-5
P(OEt)2
P(OEt)2
70%
(EtO)2P
THPO
OTHP
(EtO)2P
O
O
6
13
C6H5MgBr
CuI
C6H5MgBr
CuI
X
O
O
P(OEt)2
-
MeI
P(OEt)2
C6H5
(EtO)2P
(EtO)2P
C6H5
O
O
14
+
15
MeI, NaH
15-Cr-5
59%
11a
Scheme 4. Synthesis of a dialkyl biphosphonate.
O
O
H3C P(OEt)2
P(OEt)2
Br
LDA
99%
3
16
1) SeO2, tBuOOH, HBA
2) NaBH4
31%
O
O
C6H5MgBr
CuI
P(OEt)2
P(OEt)2
71%
RO
C6H5
DHP
91%
19
17 R = H
18 R = THP
pTsOH
RO RO
C6H5
20 R = H
21 R = CH3C(O)
Ac2O
pyridine
Scheme 5. Displacement of an allylic THP ether on a phosphonate substrate.
C6H5MgBr under standard conditions gave the dis-
placement product 19. Isolation of compound 19 was
complicated by chromatographic behavior that was
very similar to that of the by-product produced from
the THP group, the diol 20. However, after treatment
of the mixture with acetic anhydride and pyridine,
the diacetate 21 was readily separated and phosphonate
19 was isolated in 71% yield.

L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
2525
In conclusion, these studies have shown that displace-
ment of allylic THP ethers can be accomplished through
a copper-mediated displacement reaction in the presence
of a geminal bisphosphonate ester. While excess Grig-
nard reagent is required for an efficient reaction, the ini-
tial product of the displacement is an anion which, in
some cases, can be trapped by reaction with methyl io-
dide. A parallel displacement also has been demon-
3.2. Tetraethyl 4,8-dimethyl-3,7-nonadienyl-9-ol-1,1-bis-
phosphonate (5)
To a stirred suspension of SeO2 (1.34 g, 11.9 mmol)
and p-hydroxybenzoic acid (0.33 g, 2.36 mmol) in
CH2Cl2 (50 mL), geranyl bisphosphonate (4, 9.98 g,
23.5 mmol) in CH2Cl2 (20 mL) was added via cannula
at 0 °C. After the reaction was stirred for 5 min, tert-bu-
tyl hydroperoxide (13.0 mL, 93.9 mmol) was added as a
neat liquid via syringe. The reaction mixture was al-
lowed to warm to rt and stir for 18 h. The mixture
was quenched by addition of NaHCO3(sat) and ex-
tracted with Et2O. The organic portions were combined,
dried (MgSO4), and concentrated in vacuo. The result-
ing yellow oil was dissolved in methanol (200 mL) and
NaBH4 (0.89 g, 23.5 mmol) was added very slowly over
10 min at 0 °C. After 2 h, the reaction was quenched
with NH4Cl(sat) and extracted with Et2O. The com-
bined organic layers were dried (MgSO4) and concen-
trated in vacuo. A white solid (NH4Cl) emerged in the
yellow oil, which was dissolved in minimum amount of
water and extracted with Et2O, dried (MgSO4), filtered,
and concentrated in vacuo. After concentration of the
aqueous layer by a stream of air, the solid was dissolved
in a minimum amount of water and extracted with Et2O,
dried (MgSO4), filtered, and concentrated in vacuo. The
resulting yellow oil was purified by flash chromatogra-
phy (gradient, 0–10% methanol in Et2O) producing a
strated on
a phosphonate ester rather than a
bisphosphonate, suggesting that this strategy can be ap-
plied to the preparation of some variety of phosphorus
containing compounds. Other applications of this ap-
proach, as well as some studies on the biological activity
of the resulting phosphorus compounds, will be reported
in due course.
3. Experimental section
Tetrahydrofuran (THF) and diethyl ether (Et2O)
were distilled from sodium-benzophenone directly be-
fore use, while dichloromethane was distilled over cal-
cium hydride. CuI (98%) was purchased from Aldrich
and used without further purification. All nonaqueous
reactions were performed in oven-dried glassware and
beneath an atmosphere of argon. Flash chromatography
was performed using silica gel with 40 lm average par-
ticle diameter. NMR spectra were recorded on a 300
1
pale yellow oil 5 (4.54 g, 44%): H NMR d 5.40–5.30
1
MHz instrument for H (75 MHz for 13C) with CDCl3
(m, 2H), 4.22–4.11 (m, 8H), 3.96 (s, 2H), 3.06 (br s,
1H), 2.61 (tt, J = 17.4, 6.5 Hz, 2H), 2.36 (tt, J = 17.8,
6.2 Hz, 1H), 2.20–2.07 (m, 4H), 1.63 (s, 6H), 1.35 (t,
J = 7.1 Hz, 12H); 13C NMR d 136.1, 135.1, 124.5,
122.2 (t, JCP = 7.1 Hz), 68.4, 62.6 (t, JCP = 6.2 Hz,
4C), 39.2, 37.5 (t, JCP = 133.5 Hz), 25.4, 24.2 (t,
JCP = 5.0 Hz), 16.5 (d, JCP = 1.5 Hz, 2C), 16.4 (d,
JCP = 1.5 Hz, 2C), 16.0, 15.3; 31P NMR +23.1 ppm.
Anal. Calc. for C19H38O7P2: C, 51.81; H, 8.70. Found:
C, 51.47; H, 8.85%.
as the solvent and (CH3)4Si as an internal standard, un-
less otherwise stated. Chemical shifts of 31P NMR are
reported in ppm relative to 85% H3PO4 (external stan-
dard). High resolution and electron-spray mass spectra
were obtained at the University of Iowa Mass Spectrom-
etry Facility. Elemental analyses were performed by
Atlantic Microlab, Inc. (Norcross, GA).
3.1. Tetraethyl 4,8-dimethyl-3,7-nonadienyl-1,1-bisphos-
phonate (4)
3.3. Tetraethyl 4,8-dimethyl-9-(tetrahydro-pyran-2-yloxy)-
nona-3,7-dienyl-1,1-bisphosphonate (6)
To a stirred suspension of NaH (1.97 g, 49.3 mmol,
washed with hexanes and dried in vacuo) in THF (10
mL), 15-crown-5 (0.90 mL, 4.41 mmol) was added via
syringe at 0 °C over 15 min. Tetraethyl methylenebis-
phosphonate (12.3 mL, 48.3 mmol) was added as a neat
liquid to the suspension over 10 min and the reaction
mixture was allowed to stir for 30 min. The mixture
was then transferred via cannula to a stirred solution
of geranyl bromide (3, 10.0 g, 46.1 mmol) in THF (20
mL) at 0 °C. The resulting solution was stirred for 2
h, filtered through celite, and concentrated in vacuo.
The resulting yellow oil was purified by flash chroma-
tography (gradient, 0–5% methanol in Et2O) to give
To a stirred solution of bisphosphonate 5 (2.28 g,
5.17 mmol) in CH2Cl2(20 mL), DHP (1.25 mL, 13.3
mmol) was added as a neat liquid at 0 °C. After 5
min, a catalytic amount of p-TsOH (0.02 g, 0.10 mmol)
was added neat and the mixture was allowed to warm to
rt over 3.5 h. The reaction was quenched by addition of
NaHCO3(sat) and extracted with Et2O. The combined
organic layers were dried (MgSO4) and concentrated
in vacuo to provide a yellow oil. This oil was purified
by flash chromatography (3% methanol in Et2O) to af-
1
ford a pale yellow oil 6 (2.61 g, 96%): H NMR d 5.42
(t, J = 6.9 Hz, 1H), 5.33 (t, J = 7.0 Hz, 1H), 4.60 (t,
J = 3.9 Hz, 1H), 4.17 (p, J = 7.2 Hz, 8H), 4.10 (d,
1
the desired product 4 (13.9 g, 84%) with H, 13C, and
31P spectra identical to literature data [13,15].

2526
L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
J = 11.8 Hz, 1H), 3.92–3.82 (m, 2H), 3.54–3.46 (m, 1H),
2.64 (tt, J = 17.2, 6.6 Hz, 2H), 2.32 (tt, J = 23.7, 6.1 Hz,
1H), 2.18–2.01 (m, 4H), 1.89–1.51 (m, 12H), 1.34 (t,
J = 7.0 Hz, 12H); 13C NMR d 136.6, 132.1, 127.7,
122.1 (t, JCP = 7.2 Hz), 97.5, 73.0, 62.6–62.4 (m, 4C),
62.2, 39.4, 37.6 (t, JCP = 132.8 Hz), 30.7, 26.3, 25.6,
24.1 (t, JCP = 4.8 Hz), 19.6, 16.6–16.4 (m, 4C),
16.2, 14.1; 31P NMR +23.4 ppm. Anal. Calc. for
C24H46O8P2 Æ 0.5H2O: C, 54.02; H, 8.88. Found: C,
54.36; H, 8.89%.
8 as a pale yellow oil (1.34 g, 54%): 1H NMR d 5.40–5.36
(m, 1H), 5.28 (t, J = 6.9 Hz, 1H), 3.95 (br s, 2H), 3.82 (d,
J = 2.7 Hz, 6H), 3.79 (d, J = 2.7 Hz, 6H), 3.53 (br s, 1H),
2.63 (tt, J = 17.4, 6.6 Hz, 2H), 2.40 (tt, J = 24.1, 5.4 Hz,
2H), 2.19–2.04 (m, 4H), 1.64 (s, 6H); 13C NMR d 136.7,
135.0, 124.3, 121.4 (t, JCP = 7.1 Hz), 68.4, 53.2–53.0 (m,
4C), 39.0, 36.4 (t, JCP = 133.7 Hz), 25.4, 23.9 (t,
JCP = 5.1 Hz), 15.8, 13.6; 31P NMR +25.5 ppm. Anal.
Calc. for C15H30O7P2 Æ 0.5 H2O: C, 45.80; H: 7.94.
Found: C, 45.38; H, 7.89%.
3.4. Tetramethyl 4,8-dimethyl-3,7-nonadienyl-1,1-bisphos-
phonate (7)
3.6. Tetramethyl 4,8-dimethyl-9-(tetrahydro-pyran-2-
yloxy)-nona-3,7-dienyl-1,1-bisphosphonate (9)
To a stirred suspension of NaH (373.9 mg, 9.35
mmol, washed with hexanes and dried in vacuo) in
THF (30 mL), 15-crown-5 (0.17 mL, 0.84 mmol) was
added via syringe at 0 °C over 15 min. Tetramethyl
methylenebisphosphonate (2.04 g, 8.78 mmol) was
added as a neat liquid to the suspension over 10 min,
and the reaction mixture was allowed to stir for 1 h.
Geranyl bromide (3, 1.8 mL, 9.45 mmol) was added as
a neat liquid at 0 °C over 10 min. The resulting solution
was stirred for 1 h, quenched by addition of NH4Cl(sat),
and extracted with Et2O. The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo.
The resulting yellow oil was purified by flash chroma-
tography (gradient, 5–9% methanol in Et2O) to give
To a stirred solution of bisphosphonate 8 (628.8 mg,
1.64 mmol) in CH2Cl2, DHP (0.40 ml, 4.25 mmol) was
added as a neat liquid at 0 °C. After 5 min, a catalytic
amount of p-TsOH (0.02 g, 0.09 mmol) was added and
the mixture was allowed to warm to rt and stirred for
2 d. The reaction was quenched by addition of NaH-
CO3(sat) and extracted with Et2O. The combined organic
layers were dried (MgSO4) and concentrated in vacuo to
provide a yellow oil. Final purification of this oil by
flash chromatography (10% methanol in Et2O) afforded
1
compound 9 as a pale yellow oil (712 mg, 93%): H
NMR d 5.41 (t, J = 5.6 Hz, 1H), 5.28 (t, J = 6.9 Hz,
1H), 4.60–4.58 (m, 1H), 4.10 (d, J = 11.4 Hz, 1H),
3.91–3.79 (m, 2H), 3.83 (d, J = 1.8 Hz, 6H), 3.80 (d,
J = 1.8 Hz, 6H), 3.58–3.46 (m, 1H), 2.63 (tt, J = 17.2,
6.5 Hz, 2H), 2.38 (tt, J = 24.0, 5.6 Hz, 1H), 2.19–2.02
(m, 4H), 1.89–1.79 (m, 1H), 1.76–1.54 (m, 11H); 13C
NMR d 137.1, 132.1, 127.5, 121.6 (t, JCP = 7.2 Hz),
97.4, 72.9, 62.1, 53.3–53.1 (m, 4C), 39.3, 36.6 (t,
JCP = 133.2 Hz), 30.7, 26.3, 25.5, 24.0 (t, JCP = 5.1
Hz), 19.6, 16.1, 14.1; 31P NMR +25.7 ppm. Anal. Calc.
for C20H38O8P2 Æ 0.5H2O: C, 50.31; H, 8.23. Found: C,
50.30; H, 8.21%.
1
the desired product 7 (1.43 g, 45%): H NMR d 5.27
(t, J = 6.8 Hz, 1H), 5.09 (t, J = 5.5 Hz, 1H), 3.83 (d,
J = 1.7 Hz, 6H), 3.80 (d, J = 1.7 Hz, 6H), 2.64 (tt,
J = 17.2, 6.6 Hz, 2H), 2.38 (tt, J = 24.0, 6.6 Hz, 1H),
2.09–2.01 (m, 4H), 1.68 (s, 3H), 1.65 (s, 3H), 1.60 (s,
3H); 13C NMR d 137.1, 131.2, 123.9, 121.2 (t,
JCP = 7.2 Hz), 53.1–52.9 (m, 4C), 39.5, 36.5 (t,
JCP = 133.1 Hz), 26.4, 25.5, 23.8 (t, JCP = 5.0 Hz),
17.5, 15.9; 31P NMR +25.7 ppm. Anal. Calc. for
C15H30O6P2: C, 48.91; H, 8.21. Found: C, 48.74; H,
8.31%.
3.7. General procedure for copper-mediated Grignard dis-
placement of allylic THP ethers
3.5. Tetramethyl 4,8-dimethyl-3,7-nonadienyl-9-ol-1,1-bis-
phosphonate (8)
3.7.1. Aryl Grignard reagents
Magnesium metal (10 eq) was ground in a mortar and
pestle and then placed in a round bottom flask with a
Teflon stirbar and flame dried. After the flask had
cooled to rt, the magnesium was covered in a minimum
amount of ether and the bromide (10 eq) and a crystal of
I2 were added. After the solution ceased to boil, the
reaction mixture was heated to reflux for approximately
30 min and allowed to cool to rt. In a separate flask, the
THP ether (1.0 eq) was dissolved in a THF (usually ꢀ10
mL) and CuI (1.5 eq) was added. The copper-THP
solution was warmed to 35 °C and the Grignard reagent
was transferred via cannula. The reaction mixture was
heated to 50–55 °C for 1–3 h. The reaction was
quenched by the addition of 10 mL of 10% NH4OH in
Under conditions parallel to those used for prepara-
tion of the tetraethyl ester 5, the bisphosphonate 7
(2.38 g, 6.47 mmol) was treated with SeO2 (373.3 mg,
3.30 mmol), p-hydroxybenzoic acid (96.7 mg, 0.69
mmol), and tert-butyl hydroperoxide (70% in water,
3.6 mL, 26.0 mmol). After standard work-up and treat-
ment with NaBH4 (352.4 mg, 9.32 mmol), the reaction
was quenched with NH4Cl(sat), concentrated under a
stream of air, dissolved in a minimum amount of water,
and placed in a continuous liquid–liquid extractor
(Et2O) for 3 h. The organic layer was concentrated in
vacuo to a yellow oil that was purified by flash chroma-
tography (8% methanol in Et2O) to produce compound

L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
2527
NH4Cl, extracted with ether, dried (MgSO4), and con-
centrated in vacuo. Final purification was conducted
by column chromatography on silica gel with gradient
elution (2–6% CH3OH in ether).
JCP = 7.4 Hz, 4C), 46.1, 39.8, 37.8 (t, JCP = 31.9 Hz),
26.8, 24.3 (t, JCP = 4.8 Hz), 16.6 (d, JCP = 6.5 Hz, 4C),
16.3, 16.0; 31P NMR +23.5 ppm.
3.11. Tetraethyl 4,8-dimethyl-9-(m-methoxy-phenyl)-
nona-3,7-dienyl-1,1-bisphosphonate (11d)
3.7.2. Alkyl Grignard reagents
After preparation of the reagents as described above,
the copper-THP solution was cooled to À35 °C and the
solution of the Grignard reagent was transferred via
cannula over 1 h. The reaction mixture was allowed to
warm to À10 °C for 2 d. The reaction was allowed to
warm to rt, quenched, and the product was purified as
described above.
1
163 mg, 60%; H NMR d 7.19 (dt, J = 7.5, 0.9 Hz,
1H), 6.77–6.72 (m, 3H), 5.33 (t, J = 7.5 Hz, 1H), 5.25
(t, J = 7.5 Hz, 1H), 4.23–4.12 (m, 8H), 3.79 (s, 3H),
2.65 (tt, J = 17.2, 6.4 Hz, 2H), 2.32 (tt, J = 23.8, 6.0
Hz, 1H), 2.16–2.01 (m, 4H), 1.65 (s, 3H), 1.61 (s, 2H),
1.53 (s, 3H), 1.34 (dt, J = 6.7, 0.7 Hz, 12H); 31P NMR
+23.5 ppm. Anal. Calc. for C26H44P2O7 Æ 1H2O: C,
56.92; H, 8.45. Found: C, 56.94; H, 8.46%.
3.8. Tetraethyl 4,8-dimethyl-9-phenyl-nona-3,7-dienyl-1,1-
bisphosphonate (11a)
3.12. Tetraethyl 9-biphenyl-4,8-dimethyl-nona-3,7-dienyl-
1,1-bisphosphonate (11e)
1
263 mg, 86%; H NMR d 7.30–7.14 (m, 5H), 5.34 (t,
J = 6.9 Hz, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.22–4.12 (m,
8H), 3.27 (s, 2H), 2.65 (tt, J = 17.1, 6.6 Hz, 2H), 2.32 (tt,
J = 23.8, 5.9 Hz, 1H), 2.17–2.02 (m, 4H), 1.65 (s, 3H),
1.52 (s, 3H), 1.34 (dt, J = 7.0, 0.7 Hz, 12H); 13C NMR
d 140.4, 136.6, 134.5, 128.8 (2C), 128.2 (2C), 126.2,
125.9, 122.1 (t, JCP = 7.2 Hz), 62.6–62.4 (m, 4C), 46.3,
39.7, 37.6 (t, JCP = 132.9 Hz), 26.6, 24.1 (t, JCP = 4.9
Hz), 16.5 (d, JCP = 5.9 Hz, 4C), 16.1, 15.8; 31P NMR
+23.6 ppm. Anal. Calc. for C25H42O6P2: C, 59.99; H,
8.46. Found: C, 59.69; H, 8.52%.
1
258 mg, 76%; H NMR d 7.60–7.57 (m, 2H), 7.53–
7.50 (m, 2H), 7.44–7.39 (m, 2H), 7.34–7.28 (m, 1H),
7.24–7.22 (m, 2H), 5.35 (t, J = 7.0 Hz, 1H), 5.28 (dt,
J = 6.8, 1.1 Hz, 1H), 4.22–4.11 (m, 8H), 3.31 (br s,
2H), 2.66 (tt, J = 17.1, 6.9 Hz, 2H), 2.33 (tt, J = 23.8,
5.9 Hz, 1H), 2.19–2.04 (m, 4H), 1.66 (s, 3H), 1.56 (s,
3H), 1.33 (dt, J = 7.0, 0.58 Hz, 12H); 13C NMR d
146.0, 139.7, 139.0, 136.8, 134.5, 129.4 (2C), 128.8
(2C), 127.2 (2C), 127.1 (2C), 127.1, 126.5, 122.2 (t,
JCP = 7.2 Hz), 62.7–62.5 (m, 4C), 46.0, 39.8, 37.8 (t,
JCP = 132.8 Hz), 26.8, 24.3 (t, JCP = 5.0 Hz), 16.6 (d,
JCP = 5.8 Hz, 4C), 16.3, 16.0; 31P NMR +23.7 ppm.
Anal. Calc. for C31H46O6P2: C, 64.57; H, 8.04. Found:
C, 64.40; H, 8.11%.
3.9. Tetraethyl 4,8-dimethyl-9-m-tolyl-nona-3,7-dienyl-1,1-
bisphosphonate (11b)
1
236 mg, 77%; H NMR d 7.19–7.13 (m, 1H), 7.01–
6.94 (m, 3H), 5.34 (t, J = 6.9 Hz, 1H), 5.24 (t, J = 5.8
Hz, 1H), 4.22–4.12 (m, 8H), 3.23 (br s, 2H), 2.65 (tt,
J = 17.2, 6.1 Hz, 2H), 2.42–2.22 (m, 4H), 2.17–2.02
(m, 4H), 1.66 (s, 3H), 1.54 (s, 3H), 1.34 (dt, J = 7.0,
0.6 Hz, 12H); 13C NMR d 140.4, 137.7, 136.8, 134.6,
129.7, 128.2, 126.7, 129.1, 125.9, 122.1 (t, JCP = 7.2
Hz), 62.6–62.4 (m, 4C), 46.3, 39.7, 37.7 (t, JCP = 132.8
Hz), 26.7, 24.2 (t, JCP = 4.9 Hz), 21.5, 16.5 (d,
JCP = 6.4 Hz, 4C), 16.2, 15.9; 31P NMR +23.6 ppm.
Anal. Calc. for C26H44O6P2 Æ 0.5H2O: C, 59.64; H,
8.66. Found: C, 59.39; H, 8.70%.
3.13. Tetraethyl 4,8-dimethyl-10-phenyl-deca-3,7-dienyl-
1,1-bisphosphonate (11f)
1
149 mg, 75%; H NMR d 7.30–7.15 (m, 5H), 5.31 (t,
J = 6.8 Hz, 1H), 5.12 (t, J = 6.8 Hz, 1H), 4.17 (p, J = 7.6
Hz, 8H), 2.72–2.56 (m, 4H), 2.41–2.21 (m, 3H), 2.10–
1.95 (m, 4H), 1.64 (s, 6H), 1.33 (t, J = 7.0 Hz, 12H);
13C NMR d 142.3, 136.6, 134.4, 128.3 (2C), 128.1
(2C), 125.5, 124.5, 121.9 (t, JCP = 7.1 Hz), 62.4–62.2
(m, 4C), 41.5, 39.5, 37.5 (t, JCP = 132.8 Hz), 34.7,
26.4, 24.0 (t, JCP = 4.9 Hz), 16.4 (d, JCP = 6.4 Hz, 4C),
16.0 (2C); 31P NMR d +23.5 ppm. Anal. Calc. for
C21H34O6P2 Æ 0.5H2O: C, 55.62; H, 7.78. Found: C,
55.69; H, 7.93%.
3.10. Tetraethyl 4,8-dimethyl-9-(m-trifluoromethyl-phenyl)-
nona-3,7-dienyl-1,1-bisphosphonate (11c)
1
234 mg, 70%; H NMR d 7.46–7.33 (m, 4H), 5.34 (t,
J = 6.7 Hz, 1H), 5.26 (t, J = 6.8 Hz, 1H), 4.22–4.12 (m,
8H), 3.32 (s, 2H), 2.65 (tt, J = 17.0, 7.0 Hz, 2H), 2.31 (tt,
J = 23.8, 6.0 Hz, 1H), 2.18–2.02 (m, 4H), 1.65 (s, 6H),
1.33 (t, J = 7.1 Hz, 12H); 13C NMR d 141.6, 136.7,
133.8, 132.4 (d, JCP = 1.4 Hz), 128.8, 127.4, 125.6 (q,
JCF = 3.8 Hz), 124.5 (q, JCF = 270.5 Hz), 123.0 (q,
JCF = 3.8 Hz), 122.3 (t, JCP = 7.1 Hz), 62.7 (t,
3.14. Tetraethyl 4,8,12-trimethyl-trideca-3,7-dienyl-1,1-
bisphosphonate (11g)
1
114 mg, 57%; H NMR d 5.32 (t, J = 6.9 Hz, 1H),
5.09 (t, J = 6.2 Hz, 1H), 4.15 (p, J = 7.3 Hz, 8H), 2.64
(tt, J = 17.1, 6.7 Hz, 2H), 2.31 (tt, J = 23.8, 6.2 Hz,
1H), 2.07–1.90 (m, 6H), 1.65 (s, 3H), 1.58–1.48 (m,

2528
L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
4H), 1.39–1.30 (m, 14H), 1.16–1.09 (m, 2H), 0.87 (d,
J = 6.6 Hz, 6H); 13C NMR d 137.0, 135.6, 123.9, 122.0
(t, JCP = 7.1 Hz), 62.7–62.5 (m, 4C), 40.1, 39.9, 38.7,
37.7 (t, JCP = 133.0 Hz), 28.0, 26.7, 25.9, 24.2 (t,
JCP = 5.0 Hz), 22.8 (2C), 16.6 (d, JCP = 6.3 Hz, 4C),
16.3, 16.0; 31P NMR d +23.5 ppm. Anal. Calc. for
C24H48O6P2 Æ 0.5H2O: C, 57.24; H, 9.81. Found: C,
57.42; H, 9.97%.
4H), 1.86–1.50 (m, 12H), 1.33 (dt, J = 7.1, 1.5 Hz,
15H); 13C NMR d 137.7, 132.1, 127.9, 119.4 (t,
JCP = 7.3 Hz), 97.6, 73.1, 62.8–62.6 (m, 4C), 62.3, 41.2
(t, JCP = 134.0 Hz), 39.8, 31.1 (t, JCP = 4.4 Hz), 30.8,
26.5, 25.7, 19.7, 16.7–16.6 (m, 4C), 16.4, 16.3 (t,
JCP = 6.8 Hz), 14.2; 31P NMR +27.1 ppm. Anal. Calc.
for C25H48O8P2 Æ 0.5H2O: C, 54.83; H, 9.02. Found: C,
54.43; H, 8.93%.
3.15. Tetraethyl (12R)-4,8,12,16-tetramethyl-heptadeca-
3,7,15-trienyl-1,1-bisphosphonate (11h)
3.18. Tetraethyl 1,4,8-trimethyl-9-phenyl-nona-3,7-dienyl-
1,1-bisphosphonate (14)
1
14.8 mg, 19%; H NMR d 5.31 (t, J = 6.9 Hz, 1H),
Solid CuI (360 mg, 1.85 mmol) was added to a stirred
solution of THP ether 6 (644 mg, 1.23 mmol) in THF
(20 mL) at 35 °C. Phenylmagnesium bromide (12.5
mL, 0.98 M), was added via syringe to the suspension
at 50 °C. After 1.5 h, the reaction appeared to be com-
plete by TLC and CH3I (2.0 mL, 32.0 mmol) was added
as a neat liquid. The resulting solution was allowed to
stir for 10 min until a color change occurred. A solution
of 10% NH4OH in NH4Cl was added and the mixture
was extracted with Et2O. The combined organic layers
were then dried (MgSO4) and concentrated in vacuo.
Flash column chromatography (1% methanol in ethyl
acetate) resulted in a 1:1 mixture of non-methylated
and methylated products, 11a and 14, respectively. This
mixture was dissolved in THF (20 mL) and treated with
NaH (48 mg, 1.21 mmol) and CH3I (0.15 mL, 2.40
mmol), and then quenched by addition of NH4Cl
(sat). The reaction mixture was then extracted with
Et2O, dried (MgSO4), and concentrated in vacuo. Puri-
fication of the residue by flash column chromatography
(1% methanol in ethyl acetate) afforded compound 14
5.10 (t, J = 7.1 Hz, 2H), 4.17 (p, J = 7.2 Hz, 8H), 2.64
(tt, J = 18.2, 5.9 Hz, 2H), 2.31 (tt, J = 23.8, 6.2 Hz,
1H), 2.10–1.90 (m, 8H), 1.68 (s, 3H), 1.65 (s, 3H), 1.60
(s, 3H), 1.58 (s, 3H), 1.48–1.00 (m, 17H), 1.18–1.05
(m, 2H), 0.86 (d, J = 6.5 Hz, 3H); 13C NMR d 137.1,
135.7, 131.1, 125.2, 124.0, 121.9 (JCP = 7.2 Hz), 62.8–
62.6 (m, 4C), 40.2, 40.0, 37.7 (t, JCP = 132.9 Hz), 37.3,
36.8, 32.5, 31.1, 26.7, 25.9, 25.8, 25.5, 24.2 (t, JCP = 5.0
Hz), 19.8, 16.6 (d, JCP = 6.2 Hz, 4C), 16.3, 16.0; 31P
NMR d +23.5 ppm. Anal. Calc. for C29H56O6P2 Æ
0.5H2O: C, 60.90; H, 10.05. Found: C, 60.65; H, 9.99%.
3.16. Tetramethyl 4,8-dimethyl-9-phenyl-nona-3,7-dienyl-
1,1-bisphosphonate (12)
1
193 mg, 52%; H NMR d 7.30–7.14 (m, 5H), 5.31–
5.21 (m, 2H), 3.82 (d, J = 1.7 Hz, 6H), 3.79 (d, J = 1.7
Hz, 6H), 3.27 (s, 2H), 2.64 (tt, J = 17.2, 6.7 Hz, 2H),
2.37 (tt, J = 24.0, 5.8 Hz, 1H), 2.20–2.03 (m, 4H), 1.65
(s, 3H), 1.53 (s, 3H); 13C NMR d 140.5, 137.4, 134.7,
129.0 (2C), 128.3 (2C), 126.2, 126.1, 121.7 (t, JCP = 7.2
Hz), 53.3 (t, JCP = 6.2 Hz, 4C), 46.4, 39.8, 36.8 (t,
JCP = 133.2 Hz), 26.7, 24.1 (t, JCP = 5.0 Hz), 16.2,
15.9; 31P NMR +25.9 ppm. Anal. Calc. for
C21H34O6P2 Æ 0.5H2O: C, 55.62; H, 7.78. Found: C,
55.69; H, 7.93%.
1
(368 mg, 58%): H NMR d 7.29–7.14 (m, 5H), 5.42 (t,
J = 7.2 Hz, 1H), 5.25 (t, J = 5.6 Hz, 1H), 4.19 (p,
J = 7.1 Hz, 8H), 3.26 (s, 2H), 2.63 (dt, J = 15.6, 7.5
Hz, 2H), 2.17–2.02 (m, 4H), 1.64 (s, 3H), 1.52 (s, 3H),
1.40 (t, J = 16.6 Hz, 3H), 1.33 (dt, J = 7.1, 1.4 Hz,
12H); 13C NMR d 140.2, 137.4, 134.2, 128.6 (2C),
128.0 (2C), 126.1, 125.7, 119.1 (t, JCP = 7.1 Hz), 62.4–
62.3 (m, 4C), 46.1, 40.9 (t, JCP = 133.9 Hz), 39.8, 30.9
(t, JCP = 4.3 Hz), 26.5, 16.4–16.3 (m, 4C), 16.1, 16.1 (t,
JCP = 6.0 Hz), 15.6; 31P NMR +27.0 ppm. Anal. Calc.
for C26H44O6P2 Æ 0.5H2O: C, 59.64; H, 8.66. Found: C,
59.34; H, 8.66%.
3.17. Tetraethyl 1,4,8-trimethyl-9-(tetrahydro-pyran-2-
yloxy)-nona-3,7-dienyl-1,1-bisphosphonate (13)
To a stirred solution of THP ether 6 (601 mg, 1.15
mmol) in THF (20 mL), 15-crown-5 (0.01 mL, 0.05
mmol) and NaH (63 mg, 1.56 mmol) were added at 0
°C. After 30 min, CH3I (0.08 mL, 1.28 mmol) was added
as a neat liquid and the reaction mixture was stirred for
1 h. The reaction mixture was then quenched by addi-
tion of NH4Cl(sat), extracted with Et2O, dried (MgSO4),
and concentrated in vacuo. Purification by flash column
chromatography (2% methanol in Et2O) afforded com-
pound 13 (430 mg, 70%): 1H NMR d 5.44–5.37 (m,
2H), 4.61–4.58 (m, 1H), 4.23 (p, J = 7.1 Hz, 8H), 4.10
(d, J = 11.5 Hz, 1H), 3.92–3.82 (m, 2H), 3.54–3.47 (m,
1H), 2.61 (dt, J = 15.6, 7.5 Hz, 2H), 2.20–2.04 (m,
3.19. Diethyl 4,8-dimethyl-3,7-nonadienyl-1-phosphonate
(16)
To a stirred suspension of LDA [27.91 mmol, pre-
pared in situ from diisopropylamine (4.0 mL) and n
BuLi (12.35 mL, 2.38 M in hexane)] in THF (20 mL)
was added dimethyl methylphosphonate (4.0 mL, 26.6
mmol) via syringe at À78 °C over 1 h. The solution
was permitted to warm to rt and geranyl bromide (3,

L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
2529
5.4 mL, 27.2 mmol) was added as a neat liquid at 0 °C.
The resulting solution was stirred for 1 h, quenched by
the addition of NH4Cl (sat), and extracted with Et2O.
The combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo. The resulting yellow
oil was purified by flash chromatography (1% methanol
in Et2O) to afford phosphonate 16 [16] (7.58 g, 99%): 1H
NMR d 5.15–5.06 (m, 2H), 4.19–4.01 (m, 4H), 2.35–2.23
(m, 2H), 2.08–1.98 (m, 4H), 1.81–1.70 (m, 2H), 1.68 (s,
3H), 1.62 (s, 3H), 1.60 (s, 3H), 1.32 (t, J = 7.1 Hz,
6H); 13C NMR d 136.4, 131.5, 124.3, 123.2 (d,
JCP = 17.3 Hz), 61.5 (d, JCP = 6.5 Hz, 2C), 39.7, 26.7,
25.8 (d, JCP = 162.1 Hz), 25.2, 21.1 (d, JCP = 4.6 Hz),
17.8, 16.6 (d, JCP = 6.0 Hz, 2C), 16.1; 31P NMR +31.6
ppm. Anal. Calc. for C15H29O3P Æ 0.5H2O: C, 60.59;
H, 10.17. Found: C, 60.75; H, 9.97%.
3.45 (m, 1H), 2.35–2.23 (m, 2H), 2.18–2.00 (m, 4H),
1.89–1.70 (m, 4H), 1.65 (s, 3H), 1.62 (s, 3H), 1.61–1.48
(m, 3H), 1.33 (t, J = 7.1 Hz, 6H), 1.28–1.09 (m, 1H);
13C NMR d 136.1, 132.1, 127.6, 123.4 (d, JCP = 17.4
Hz), 97.4, 72.9, 62.2, 61.5 (d, JCP = 6.5, 2C), 39.2,
30.7, 26.3, 26.0 (d, JCP = 138.7 Hz), 25.6, 21.1 (d,
JCP = 4.6 Hz), 19.6, 16.6 (d, JCP = 6.0 Hz, 2C), 16.0,
14.1; 31P NMR +31.5 ppm. Anal. Calc. for
C20H37O5P: C, 61.84; H, 9.60. Found: C, 61.74; H,
9.70%.
3.22. Diethyl 4,8-dimethyl-9-phenyl-nona-3,7-dienyl-1-
phosphonate (19)
To a stirred solution of phosphonate 18 (402 mg,
1.04 mmol) in CH2Cl2(21 mL), copper iodide (310
mg, 1.60 mmol) was added at 35 °C. Once the temper-
ature reached 50 °C, phenyl magnesium bromide (0.98
M in THF, 10.8 ml, 10.5 mmol) was added and the
mixture stirred until the starting material had been con-
sumed. The reaction mixture was allowed to cool to rt
and quenched by the addition of 20 mL of 10%
NH4OH in NH4Cl(sat). The mixture was extracted with
ether, dried (MgSO4), filtered, and concentrated in va-
cuo. The crude mixture was purified by flash chroma-
tography (Et2O) to provide a pale yellow oil as a
single spot by TLC. Analysis by 1H NMR indicated
the presence of both diol 20 and the desired product
19. The mixture was dissolved in pyridine (10 mL)
and acetic anhydride (3.0 mL) was added at rt. After
stirring overnight, the reaction was quenched by addi-
tion of NH4Cl (sat) and extracted with Et2O. The com-
bined organic layers were washed repeated with NiCl2
(2.0 M) to remove pyridine, until the aqueous layer re-
mained green. The resulting organic layer was dried
(MgSO4), filtered, and concentrated in vacuo. The mix-
ture was purified by flash chromatography (gradient,
30% Et2O in hexane to 1% methanol in Et2O) to pro-
vide two oils, phosphonate 19 (246 mg, 71%) and the
diacetate 21 (240 mg, 88%).
3.20. Diethyl 4,8-dimethyl-3,7-nonadienyl-9-ol-1-phospho-
nate (17)
According to the procedure described for bisphos-
phonate 5, the geranyl phosphonate 16 (2.61 g, 9.0
mmol) was treated with SeO2 (518 mg, 4.67 mmol), p-
hydroxybenzoic acid (129 mg, 0.93 mmol) and tert-butyl
hydroperoxide (70% in water, 5.0 mL, 36.1 mmol). After
standard work-up and treatment with NaBH4 (352 mg,
9.3 mmol) in methanol, the resulting yellow oil was puri-
fied by flash chromatography (2 % methanol in Et2O) to
afford compound 17 as a pale yellow oil (854 mg, 31%):
1H NMR d 5.37 (t, J = 6.5 Hz, 1H), 5.15 (t, J = 6.8 Hz,
1H), 4.14–4.00 (m, 4H), 3.94 (s, 2H), 2.34–2.22 (m, 2H),
2.14–2.02 (m, 4H), 1.81–1.70 (m, 2H), 1.63 (s, 3H), 1.62
(s, 3H), 1.32 (t, J = 7.1 Hz, 6H); 13C NMR d 135.9,
135.2, 124.4, 123.1 (d, JCP = 15.6 Hz), 68.0, 61.4 (d,
JCP = 6.5 Hz, 2C), 39.2, 26.0, 25.7 (d, JCP = 139.2 Hz),
20.9 (d, JCP = 4.7 Hz), 16.4 (d, JCP = 6.0 Hz, 2C),
15.9, 13.6; 31P NMR +31.5 ppm. Anal. Calc. for
C15H29O4P Æ 0.33H2O: C, 58.06; H, 9.63. Found: C,
58.33; H, 9.55%.
3.21. Diethyl 4,8-dimethyl-9-(tetrahydro-pyran-2-yloxy)-
nona-3,7-dienyl-1-phosphonate (18)
1
For phosphonate 19: H NMR d 7.29–7.14 (m, 5H),
5.23–5.19 (m, 1H), 5.16–5.11 (m, 1H), 4.16–4.03 (m,
4H), 2.35–2.23 (m, 2H), 2.16–2.00 (m, 4H), 1.80–1.69
(m, 2H), 1.62 (s, 3H), 1.52 (s, 3H), 1.32 (t, J = 7.1 Hz,
6H); 13C NMR d 140.4, 136.2 (d, JCP = 1.8 Hz), 134.5,
128.8 (2C), 128.2 (2C), 126.2, 125.9, 123.3 (d,
JCP = 17.5 Hz), 61.4 (d, JCP = 6.5, 2C), 46.3, 39.5,
26.5, 26.0 (d, JCP = 138.7 Hz), 21.1 (d, JCP = 4.6 Hz),
16.5 (d, JCP = 6.0 Hz, 2C), 16.0, 15.8; 31P NMR +31.6
To a stirred solution of phosphonate 17 (2.26 g, 7.42
mmol) in CH2Cl2 (40 mL), DHP (1.75 mL, 18.6 mmol)
was added as a neat liquid at 0 °C. After 5 min, a cata-
lytic amount of p-TsOH (0.03 g, 0.16 mmol) was added
as a neat solid and the mixture was allowed to warm to
rt and stir for 2 d. The reaction was quenched by addi-
tion of NaHCO3(sat) and extracted with Et2O. The
combined organic layers were dried (MgSO4) and con-
centrated in vacuo to provide a yellow oil. Final purifi-
cation by flash chromatography (1% methanol in Et2O)
gave compound 18 as a pale yellow oil (2.58 g, 91%): 1H
NMR d 5.42–5.38 (m, 1H), 5.16–5.12 (m, 1H), 4.61–4.58
(m, 1H), 4.18–4.01 (m, 5H), 3.91–3.82 (m, 2H), 3.54–
1
ppm. For compound 21: H NMR d 7.32–7.24 (m, 5H),
5.73 (dd, J = 7.6, 6.2 Hz, 1H), 4.01 (t, J = 6.6 Hz, 2H),
2.04 (s, 3H), 1.99 (s, 3H), 1.98–1.75 (m, 2H), 1.67–1.58
(m, 2H), 1.48–1.21 (m, 2H); 13C NMR d 170.9, 170.1,
140.5, 128.4 (2C), 127.9, 126.4 (2C), 75.7, 64.0, 35.8,
28.2, 21.9, 21.2, 20.9.

2530
L.W. Shull, D.F. Wiemer / Journal of Organometallic Chemistry 690 (2005) 2521–2530
Acknowledgements
Sawyer, W.C. Shakespeare, S.M. Violette, M. Weigele, J. Med.
Chem. 44 (2001) 660–663.
[8] (a) H. Shinoda, G. Adamek, R. Felix, H. Fleisch, R. Schenk, P.
Hagan, Calcif. Tiss. Int. 35 (1983) 87–99;
We thank Matthew Buller for his assistance with
preparation of compounds 11c and 11d. Financial sup-
port from the Roy J. Carver Charitable Trust is grate-
fully acknowledged.
(b) F.H. Ebetino, A.V. Bayless, J. Amburgey, K.J. Ibbotson, S.
Dansereau, A. Ebrahimpour, Phosphorus, Sulfur and Silicon 110
(1996) 217–220;
(c) E. van Beek, C. Lowik, I. Que, S. Papapoulos, J. Bone Miner.
Res. 11 (1996) 1492–1497.
References
[9] M.F. Mechelke, D.F. Wiemer, J. Org. Chem. 64 (1999) 4821–
4829.
[1] For a recent review see: R.G.G. Russell, Phosphorus, Sulfur and
Silicon 146 (1999) 793–820.
[10] T.W. Greene, P.G. Wuts, Protective Groups in Organic Synthesis,
third ed., Wiley, New York, 1999.
[2] G.R. Kieczykowski, R.B. Jobson, D.G. Melillo, D.F. Reinhold,
V.J. Grenda, I. Shinkai, J. Org. Chem. 60 (1995) 8310–8312,
and references cited therein.
[11] (a) F. Eymery, B. Iorga, P. Savignac, Tetrahedron 55 (1999)
13109–13150, and references cited therein;
(b) K. Afarinkia, H.M. Binch, C. Modi, Tetrahedron Lett. 39
(1998) 7419–7422;
[3] (a) F.H. Ebetino, C.R. Degenhardt, L.A. Jamieson, D.C. Burd-
sall, Heterocycles 30 (1990) 855–862;
(c) I.C. Baldwin, R.P. Beckett, J.M.J. Williams, Synthesis (1996)
34–36.
(b) X.H. Liu, X.R. Zhang, G.M. Blackburn, Chem. Commun.
(1997) 87–88.
[12] L.M. Lentsch, D.F. Wiemer, J. Org. Chem. 64 (1999)
5205–5212.
[4] G. Olive, F. Le Moigne, A. Mercier, P. Tordo, Synth. Commun.
30 (2000) 619–627.
[13] S.A. Holstein, D.M. Cermak, D.F. Wiemer, K. Lewis, R.J. Hohl,
Bioorg. Med. Chem. 6 (1998) 687–694.
[5] (a) G. Sturtz, J. Guervenou, Synthesis (1991) 661–662;
(b) P.C.B. Page, J.P.G. Moore, I. Mansfield, M.J. McKenzie,
W.B. Bowler, J.A. Gallagher, Tetrahedron 57 (2001) 1837–1847.
[6] (a) D.A. Nicholson, H. Vaughn, J. Org. Chem. 36 (1971) 3843–
3845;
[14] (a) K.B. Sharpless, R.F. Lauer, J. Am. Chem. Soc. 94 (1972)
7154–7155;
(b) K.B. Sharpless, M.A. Umbreit, J. Am. Chem. Soc. 99 (1977)
5526–5528.
(b) L.M. Nguyen, E. Niesor, C.L. Bentzen, J. Med. Chem. 30 (1987)
1426–1433.
[15] For some related farnesol derivatives cf: A.R.P.M. Valentijn, O.
van den Berg, G.A. van der Marel, L.H. Cohen, J.H. van Boom,
Tetrahedron 51 (1995) 2099–2108.
[7] (a) C.K. McClure, R.C. Hausel, K.B. Hansen, C.W. Grote, K.Y.
Jung, Phosphorus, Sulfur, Silicon, Relat. Elem. 111 (1996) 695;
(b) R.S. Bohacek, D.C. Dalgarno, M. Hatada, V.A. Jacobsen,
B.A. Lynch, K.J. Macek, T. Merry, C.A. Metcalf III, S.S. Narula,
[16] J.L. Montero, I. Zgani, C. Menut, V. Gallois, Fr. Demande
(2003), 118 pp. CODEN: FRXXBL FR 2833266 A1 20030613.
Application: FR 2001-15971 20011211.