Direct monoalkylation of alkyl phosphinates to access H-phosphinic acid esters

Article abstract of DOI:10.1055/s-2005-924768

Simple alkyl phosphinates prepared by the silicate esterification method can be alkylated under Barbier-like conditions with butyl lithium at -78 °C followed by warming to room temperature. The method is limited to the more reactive electrophile such as allylic bromides and alkyl iodides. With these electrophiles good yields of H-phosphinic acid esters are generally obtained in a straightforward manner. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-924768

PAPER
325
Direct Monoalkylation of Alkyl Phosphinates to Access H-Phosphinic Acid
Esters
D
irec
t
M
s
onoalkyla
a
tion of
A
lk
b
yl
P
hosphina
e
tes lle Abrunhosa-Thomas, Patrice Ribière, Alicia C. Adcock, Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, TX 76129, USA
Fax +1(817)2575851; E-mail: j.montchamp@tcu.edu
Received 1 July 2005
A few years ago, we reported a novel and high yielding
method to prepare alkyl phosphinates using alkoxysilanes
or silicates (Equation 2).6 It was found that the alkyl phos-
phinates are more robust than when prepared with the oth-
Abstract: Simple alkyl phosphinates prepared by the silicate ester-
ification method can be alkylated under Barbier-like conditions
with butyl lithium at –78 °C followed by warming to room temper-
ature. The method is limited to the more reactive electrophile such
as allylic bromides and alkyl iodides. With these electrophiles good er methods.6 We therefore set out to investigate the
yields of H-phosphinic acid esters are generally obtained in a
straightforward manner.
alkylation of these phosphinates under basic conditions,
and the results are presented herein.
Key words: phosphorus, H-phosphinic acid, phosphinates, alkyla-
tion, hypophosphite
O
P
O
P
R'xSi(OR)4–x
H
H
H
H
MO
RO
solvent, heat
~ 2 h
85–100%
In principle, the direct alkylation of alkyl phosphinates
[ROP(O)H2] under basic conditions would be an efficient
approach towards variously substituted H-phosphinic acid
esters [R¢P(O)(OR)H]. However, this approach was not
considered viable until Gallagher reported the alkylation
of isopropyl phosphinate using alkyl halides and sodium
isopropoxide (Equation 1).1 Previously, only conjugate
addition using a catalytic amount of base was demonstrat-
ed.2 The reason for the failed alkylation was proposed to
be the result of the rapid decomposition of the anion de-
rived from unhindered esters (R = Me, Et) of hypophos-
phorous acid.3 Gallagher prepared isopropyl phosphinate
using the Nifant’ev esterification method,4 and successful
alkylation was attributed to the more hindered nature of
the ester which slowed down decomposition.1 Unfortu-
nately, this method has apparently not found widespread
use, in spite of the importance of H-phosphinic acid esters
as intermediates for the preparation of various organo-
phosphorus compounds. Instead the alkylation of alkyl
phosphinate equivalents [(EtO)2CHP(O)(OEt)H, and
(EtO)2CMeP(O)(OEt)H, ‘Ciba-Geigy reagents’] has been
employed commonly even if it involves a protection–
deprotection sequence.5
M = H, PhNH3, NH4
R = Me, Et, Bu, Allyl, Ph, etc.
Equation 2
Alkyl phosphinates were prepared by our silicate method6
(Equation 2) and used in situ, since isolation of alkyl
phosphinates is not possible due to the sensitivity of these
esters. We previously showed that alkyl phosphinate solu-
tions can be used conveniently for a wide range of reac-
tions.6,7
The alkylation of ethyl phosphinate with benzyl bromide
was selected as the model reaction. Because butyl lithium
is employed, we further settled on THF as the solvent. Af-
ter some experimentation, it was found that Barbier-like
conditions in which the base is added to a mixture of the
nucleophile (alkyl phosphinate) and electrophile (alkyl
halide) in nearly stoichiometric ratios, is more satisfactory
and also experimentally simpler. Table 1 shows the re-
sults with various alkyl halides and phosphinates. Under
these conditions, ethyl H-benzylphosphinate was ob-
tained in 71% isolated yield (Table 1, entry 1). The alkyl-
ation of butyl and isopropyl phosphinates proceeded
similarly (entries 2 and 3). Benzyl phosphinate was also
benzylated successfully (entry 4) but in lower yield due to
the higher hydrolytic lability of the product during chro-
matographic purification over silica gel.8 There was no
significant difference between the preparation of the alkyl
phosphinate from H3PO2 or from anilinium hypophos-
phite.
O
P
O
P
RX, i-PrONa
H
H
O-i-Pr
R
O
H
THF, i-PrOH
r.t.
50–90%
RX = CH3I, CH2=CHCH2Br, BnBr, n-C5H11I, Br(CH2)4Br
Equation 1
Reactive electrophiles generally give good yields, but less
reactive halides are problematic (Table 1). 2-Bromoben-
zyl bromide reacted uneventfully (entry 5). Butyl iodide
still delivered an acceptable yield (entries 6 and 7), except
with benzyl phosphinate (entry 8). As expected, octyl io-
dide reacted similarly (entry 9), but the bromide was un-
satisfactory (entry 10). Although this fact represents a
SYNTHESIS 2006, No. 2, pp 0325–0331
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-924768; Art ID: M04305SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

326
I. Abrunhosa-Thomas et al.
PAPER
Table 1 Butyl Lithium Promoted Alkylation of Alkyl Phosphinates under Barbier-like Conditions
O
P
O
P
H
H
R'
n-BuLi
+ R'X
RO
RO
THF, –78 °C to r.t.
H
Entry
R
Electrophile
Product
Isolated yield (%)
O
P
1
2
3
4
Et
Benzyl bromide
71
70
65
45
OR
H
Bu
i-Pr
Bn
5
Bu
2-Bromobenzyl bromide
Butyl iodide
76
O
P
OR
H
Br
6
7
8
Et
Bu
Bn
22
51
0
O
P
OR
H
9
10
Bu
Bu
Octyl iodide
Octyl bromide
35
8
O
P
OR
H
11
12
Bu
Bn
MeI
82
76
O
OR
H3C
P
H
O
13
14
Bu
Bn
Allyl bromide
71
39
OR
H
P
15
16
Bu
Bu
Cinnamyl chloride
Cinnamyl bromide
0
60
O
P
OR
H
17
18
19
Bu
Bu
Bu
Geranyl bromide
62
80
81
O
P
OR
H
Farnesyl bromide
O
P
OR
H
2
4-Bromo-2-methyl-2-butene
O
P
OR
H
significant limitation, alkyl H-phosphinates can be ob- phinate in 55% yield.11c Methyl-H-phosphinate esters are
tained from the corresponding alkenes using methodology also available from the reaction of an alcohol with
we have developed.9
commercially
available
dichloromethylphosphine
(CH3PCl2),12 but the latter reagent is expensive and haz-
ardous. The methylation of benzyl phosphinate produces
the novel and synthetically useful intermediate 1 which
we are currently employing in a variety of synthetic appli-
cations. Scheme 1 shows an example, in connection with
a project aiming at the preparation of GABA analogues.
N,O-Bis(trimethylsilyl)acetamide (BSA)-promoted addi-
tion of reagent 1 to CBZ-protected piperidone, followed
by cleavage of the resulting silyl ether,13 produced inter-
mediate 2. Hydrogenolysis then cleanly delivered the pure
GABA analogue 3 as the zwitterion, without the need for
tedious ion-exchange chromatography. Analogue 3
showed no activity on the GABAB receptor.14 Reagent 1
can be prepared routinely in multigram quantities.
For benzylic substrates, we have also reported a palladi-
um-catalyzed cross-coupling approach.10 Another
approach11 involves the reaction of the Grignard reagent
with ClP(OR)2 but it suffers from obvious limitations, and
provides butyl benzyl-H-phosphinate in 58% yield11c
(compared to 70% in entry 2). Unfortunately, there is still
no general approach to prepare alkyl H-phosphinates from
alkyl halides. In our hands, even the Gallagher method1
(Equation 1) which reportedly works with a bromoalkane
is unsatisfactory, and this prompted the present study.
Methylation is readily accomplished with MeI. Both butyl
and benzyl methyl-H-phosphinate esters are obtained in
good yields (entries 11 and 12, respectively). For compar-
ison, the Grignard method affords butyl methyl-H-phos-
Synthesis 2006, No. 2, 325–331 © Thieme Stuttgart · New York

PAPER
Direct Monoalkylation of Alkyl Phosphinates
327
O
give any significant amounts of products include: styrene
oxide, cyclohexene oxide, ethyl iodomethylacetate, meth-
ylene iodide, N-bromomethylphthalimide, and octyl chlo-
ride. As suggested previously,3 failed alkylations can be
attributed to the decomposition of the anionic intermedi-
ate which then takes place more rapidly than the intermo-
lecular reaction with the electrophile.
O
P
CH3
H
O
1)
BnO
P
CH3
OBn
HO
1
BSA
MeCN, 1 h, reflux
N
N
CBZ
CBZ
2) Et3N⋅3HF
35–40 °C, 16 h
60%
2
O
P
During these studies, the reaction of ethyl phosphinate
with benzyl bromide was investigated with other bases.
Somewhat surprisingly, l,8-diazabicyclo[5,4,0]undec-7-
ene (DBU) in acetonitrile actually promoted alkylation in
moderate yield (Equation 3). Analysis of the reaction
mixture obtained by mixing ethyl phosphinate with DBU
CH3
O
HO
H
H2, Pd-C
2
THF–H2O (2:1)
14 h
N
H
100%
3
by 31P NMR showed a peak at d = 160 ppm (dm, JP–H
=
Scheme 1 Synthesis of a GABA analogue using reagent 1
204 Hz). This signal could correspond to the P(III) form
of ethyl phosphinate hydrogen-bonded to DBU
[(EtO)P(H)OH.DBU] or to a tight ion-pair, instead of the
fully deprotonated phosphinate anion.19 Allyl bromide
and methyl iodide also reacted similarly, however other
electrophiles only gave traces of products irrespective of
the conditions (solvent, stoichiometry, temperature). With
allyl bromide, a small amount of disubstitution was ob-
served, but the product mixture could be obtained after a
simple extractive workup (Equation 4).
The present method is particularly useful to access allylic
H-phosphinates from the corresponding bromides. Allylic
H-phosphinates have previously been obtained by the
Regan–Boyd allylation of (TMSO)2PH,15 but the reaction
is inconvenient and often produces bis-allylated products
which are difficult to separate.16 Esterification of the H-
phosphinic acid product is also required. We have shown
previously that similar products can be accessed via nick-
el-catalyzed cross-coupling but over-reduction can also
be observed.10 Gallagher has reported a single example
using allyl bromide and isopropyl phosphinate (65%
yield).1 In comparison, our present method is advanta-
geous because it is experimentally simple, does not re-
quire the preparation and manipulation of isopropyl
phosphinate (Dean–Stark, benzene removal, and solvent
exchange), can be conducted on small or large scales, and
it can produce various esters (entries 13 and 14). Cin-
namyl, geranyl, farnesyl, and prenyl bromides all reacted
in high yield (entries 16–19). Farnesyl H-phosphinate 4 is
a useful intermediate as related compounds have been pre-
pared previously through multistep synthesis.17 For exam-
ple (Scheme 2), conjugate addition with benzyl acrylate
afforded compound 5, which is similar to an intermediate
used in the synthesis of an inhibitor of Ras farnesyl pro-
tein transferase.17a Through known methods,18 4 is also a
precursor to the corresponding phosphonochloridate
which was employed in the preparation of a farnesyl py-
rophosphate analogue.17b
O
DBU (1.1 equiv)
EtO
EtOP(O)H2 + BnBr
(1.1 equiv)
P
MeCN, reflux
54%
H
Equation 3
O
P
DBU (1.1 equiv)
EtO
R
EtOP(O)H2 + AllylBr
(1.1 equiv)
MeCN, reflux
84%
R = H/R = allyl = 8.4:1
Equation 4
In conclusion, we have investigated the alkylation of alkyl
phosphinates with various electrophiles. The butyl lithium
method is straightforward and is compatible with the for-
mation of various esters of H-phosphinic acids. However,
good yields are only obtained with the more reactive elec-
trophiles such as methyl iodide and allylic bromides. With
allylic bromides this approach is currently the best avail-
able to produce the corresponding allylic H-phosphinate
esters. Benzyl methyl-H-phosphinate (reagent 1) was also
prepared for the first time and employed for the synthesis
of a GABA analogue. While a wide range of H-phosphin-
ic acid derivatives is now becoming available through var-
ious P–C bond-forming methodologies,20 the reaction of
phosphinates with unactivated alkyl halides remains a sig-
nificant and largely unresolved challenge.
O
OBu
P
H
4
O
OBu
CO2Bn
4
P
BSA, CH2Cl2, r.t.
48%
CO2Bn
5
Scheme 2
All reactions were conducted in dry glassware under N2. Organic
solutions of products were dried over MgSO4, and filtered. Aqueous
hypophosphorous acid (50 wt.%), and BuLi (1.6 M in hexanes)
were obtained from Aldrich and used as received. Concentrated hy-
pophosphorous acid was obtaining by concentrating the 50 wt.%
As mentioned above, the method is still limited to reactive
electrophiles. Alkyl bromides are not sufficiently reac-
tive, and even simple alkyl iodides only afford moderate
yields. Other electrophiles that were tested but failed to
Synthesis 2006, No. 2, 325–331 © Thieme Stuttgart · New York

328
I. Abrunhosa-Thomas et al.
PAPER
Benzyl (N-Benzyloxycarbonyl-4-piperidinyl)methylphos-
aqueous solution in vacuo on a rotary evaporator, at r.t. for 20–30
min before reaction. Anilinium hypophosphite was prepared as pre-
viously described by us.21 When anhyd solvents were used, they
were prepared as follows: THF was distilled under N2 from Na–ben-
zophenone ketyl, and used immediately; anhyd MeCN was freshly
phinate 2 (Scheme 1)
To a mixture of benzyl methyl-H-phosphinate (0.198 g, 1.3 equiv,
1.2 mmol) and N-benzyloxycarbonylpiperid-4-one (0.23 g, 1 equiv,
0.89 mmol), in anhyd MeCN (3 mL) was added BSA (0.246 mL, 1
equiv, 0.89 mmol) dropwise at r.t. The reaction mixture was re-
fluxed for 1.5 h, then cooled to r.t. Et3N–3 HF (0.064 mL, 0.4 equiv,
0.4 mmol) was added dropwise and the reaction mixture was
warmed at 35–40 °C for 18 h. The reaction mixture was quenched
with sat. aq NaHCO3 (5 mL), then washed with aq HCl (0.1 M, 5
mL), and extracted with CH2Cl2 (2 ×). The combined organic layers
were washed with brine, then dried over MgSO4 and concentrated
under vacuum. The resulting oil was purified by chromatography
over silica gel (hexanes–EtOAc, 60:40) to produce the expected
compound (0.22 g, 60%) as a viscous yellow oil.
1
distilled from CaH2. H NMR spectra were recorded on a Varian
Mercury-300 spectrometer. Chemical shifts for 1H NMR spectra are
reported (in ppm) relative to internal TMS (d = 0.00 ppm) with
CDCl3 as solvent. 13C NMR spectra were recorded on a Varian Mer-
cury-300 spectrometer at 75 MHz. Chemical shifts for 13C NMR
spectra are reported (in ppm) relative to CDCl3 (d = 77.0 ppm). 31
P
NMR spectra were recorded at 121 MHz on a Varian Mercury-300,
spectrometer and/or at 36 MHz on an Anasazi EFT-90 spectrome-
ter, and chemical shifts are reported (in ppm) relative to external
85% phosphoric acid (d = 0.0 ppm). Radial chromatography was
carried out with a Harrison Associates Chromatotron using 1, 2, or
4 mm layers of silica gel 60 PF254 containing gypsum (E. Merck).
Silica gel (200–300 mesh, Natland International Corporation) was
used for flash chromatography. EtOAc–hexanes mixtures were
used as the eluent for chromatographic purifications. TLC plates
were visualized by immersion in anisaldehyde stain (by volume:
93% EtOH, 3.5% H2SO4, 1% HOAc, and 2.5% anisaldehyde) fol-
lowed by heating. Mass spectrometry was provided by the Mass
Spectrometry Facility of the University of South Carolina.
1H NMR (300 MHz, CDCl3): d = 1.42 (t, JHP = 13.2 Hz, 3 H), 1.52–
1.87 (m, 4 H), 3.12–3.38 (m, 2 H), 3.95–4.19 (m, 2 H), 5.06–5.12
(m, 4 H), 7.30–7.41 (m, 10 H).
13C {1H} NMR (22.63 MHz, CDCl3): d = 9.04 (d, JPC = 86 Hz),
29.7, 31.0, 38.0, 38.5, 66.7 (d, JPOC = 6.3 Hz), 66.8, 69.5 (d, JPC
=
116 Hz), 127.5, 127.6, 127.8, 128.2, 128.3, 128.4, 128.5, 136.7,
155.1.
31P NMR (121.47 MHz, CDCl3): d = 56.04 (81%), 54.81 (19%).
HRMS (EI+): m/z calcd for C21H26O5PN: 404.1627; found:
404.1639.
Formation of AlkOP(O)H2; Typical Procedure
This synthesis was conducted as described in the literature.6 A solu-
tion (or suspension) of the hypophosphorous compound (5 mmol),
alkoxysilane [3.33 mmol for (RO)4Si, or 7.5 mmol for (RO)2SiMe2]
in solvent (10 mL) was refluxed for 2 h under N2. After cooling to
r.t., the reaction mixture was used for the alkylation reaction, or
stored under N2 as a stock solution.
(4-Hydroxypiperidin-4-yl)methylphosphinic Acid (3) (Scheme
1)
To a dry flask under N2 containing Pd/C (10%, 110 mg) was added
1.5 mL of a mixture of solvent H2O–THF (1:2), following by a so-
lution of the benzyl (N-benzyloxycarbonyl-4-piperidin-yl)meth-
ylphosphinate (0.197 g) in 3.5 mL of the same mixture of solvent
H2O–THF. Then reaction was shaken in a Parr apparatus, at r.t. un-
der H2 pressure (52 psi) for 15 h. The mixture was filtered through
celite and the aqueous layer was concentrated under vacuum to give
a white solid (85 mg, 100%).
1H NMR (300 MHz, CDCl3): d = 1.24 (d, JHP = 13.2 Hz, 3 H), 1.60–
2.13 (m, 4 H), 3.22–3.37 (m, 4 H).
13C {1H} NMR (22.63 MHz, CDCl3): d = 9.81 (d, JPC = 92 Hz), 26.9
(d, JPCCC = 5.2 Hz), 38.6 (d, JPCC = 8.8 Hz), 67.7 (d, JPC = 116 Hz).
31P NMR (121.47 MHz, CDCl3): d = 43.48.
Alkylation; Typical Procedure (Table 1)
To a solution of alkyl phosphinate (1.5 equiv, 1.5 mmol) and alkyl
halide (1 equiv, 1 mmol) in anhyd THF was added BuLi (1.6 M in
hexane, 1.2 equiv, 1.2 mmol), at –78 °C under N2. After the addition
of BuLi, the temperature of the solution was slowly allowed to reach
r.t. (1.5 h). Once at r.t., the reaction mixture was quenched by a so-
lution of NaHSO4 (20% in water), and extracted with EtOAc (2 ×).
The organic layer was washed with brine, dried over anhyd MgSO4
and concentrated in vacuo. The resulting oil was purified by column
chromatography over silica gel.
HRMS (EI+): m/z calcd for C6H14O3PN: 180.0789; found:
180.0782.
Benzyl Methyl-H-phosphinate (1) (Table 1, Entry 12; Scheme 1)
To a mixture of benzyl hypophosphite [prepared from (BnO)4Si] in
anhyd THF (0.6 M, 117 mL, 1.8 equiv, 70 mmol) and iodomethane
(2.4 mL, 1 equiv, 38.9 mmol), was added BuLi (c = 1.6 M in hex-
ane, 1.2 equiv, 46.7 mmol, 29.2 mL) dropwise at –78 °C, under N2.
Once the addition was complete, the reaction mixture was allowed
to warm slowly to r.t. over 2 h. The mixture was quenched with 20%
aq NaHSO4 (60 mL) and extracted with EtOAc (2 ×). The combined
organic phases were washed with brine, then dried over MgSO4 and
concentrated under vacuum. The crude oil obtained was purified by
chromatography over silica gel (MeOH–EtOAc, 5:95) to produce
the expected compound (5.0 g, 76%) as a yellow oil.
Ethyl Benzyl-H-phosphinate22 (Equation 3)
To a mixture of benzyl bromide (0.94 g, 1.1 equiv, 5.5 mmol) and a
solution of EtOP(O)H2 (10 mL, 0.5 M in MeCN, 1 equiv, 5 mmol)
in a dry flask under N2, was added DBU (0.84 g, 1.1 equiv, 5.5
mmol) at r.t. A water bath was used to prevent any increase in the
temperature. After 1 h, the mixture was quenched with a 10%
NaHSO4 solution (5 mL) and extracted with EtOAc. The combined
organic phases were washed with brine, then dried over MgSO4.
Concentration afforded the crude compound, which was purified by
silica gel chromatography (hexanes → EtOAc) to produce the ex-
pected compound (0.50 g, 54%) as a clear oil. Yield: 71%; RN:
[114425-49-9].
1H NMR (300 MHz, CDCl3): d = 1.56 (d, JHP = 3, 15 Hz, 3 H), 5.02,
5.10 (ABX system, JAB = 11.7 Hz, 2JAX = 10.5 Hz, 2JBX = 8.5 Hz, 2
H), 7.26 (d, JHP = 542 Hz, 1 H), 7.12–7.46 (m, 5 H).
1H NMR (300 MHz, CDCl3): d = 1.31 (t, J = 7 Hz, 3 H), 3.20 (dd,
JHP = 18 Hz, J = 2 Hz, 2 H), 3.95–4.20 (m, 2 H), 7.05 (dt, JHP = 544
Hz, J = 2 Hz, 1 H), 7.20–7.40 (m, 5 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 16.2 (d, JPOCC = 6 Hz),
37.0 (d, JPC = 89 Hz), 62.7 (d, JPOC = 7 Hz), 127.2 (d, JPCCCCC = 4
Hz), 128.9 (d, JPCCCC = 3 Hz), 129.7 (d, JPCCC = 6 Hz), 129.8 (d,
JPCC = 7 Hz).
13C {1H} NMR (75.45 MHz, CDCl3): d = 15.4 (d, JPC = 95 Hz), 67.8
(d, JPOC = 6 Hz), 128.4, 128.9, 129.0, 135.8 (d, JPCC = 6 Hz).
31P NMR (121.47 MHz, CDCl3): d = 35.2 (dm, JPH = 542 Hz).
HRMS (EI+): m/z calcd for C8H11O2P: 170.0497; found: 170.0491.
Synthesis 2006, No. 2, 325–331 © Thieme Stuttgart · New York

PAPER
Direct Monoalkylation of Alkyl Phosphinates
329
31P NMR (121.47 MHz, CDCl3): d = 37.52 (dm, JPH = 544 Hz).
HRMS (EI+): m/z calcd for C9H13O2P: 184.0653; found: 184.0654.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.3 Hz, 3 H), 1.30
(sext, J = 7.3 Hz, 2 H), 1.58–1.67 (m, 2 H), 3.33–3.52 (m, 2 H),
3.90, 4.16 (m, 2 H), 7.14 (m, 1 H), 7.15 (d, JHP = 552 Hz, 1 H), 7.26–
7.34 (m, 2 H), 7.57 (d, J = 8.2 Hz, 1 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 18.9, 32.5 (d,
JPOCC = 6.0 Hz), 37.4 (d, JPC = 89 Hz), 66.8 (d, JPOC = 7.5 Hz), 124.9
Ethyl Allyl-H-phosphinate5e,23 (Equation 4, Alternate Workup
Procedure)
To a mixture of allyl bromide (0.40 g, 1.1 equiv, 3.3 mmol) and a
solution of EtOP(O)H2 (6 mL, 0.5 M in MeCN, 1 equiv, 3 mmol),
was added DBU (0.49 g, 1.1 equiv, 3.3 mmol) at r.t., under N2. A
water bath was used to prevent any increase in the temperature. Af-
ter 1 h, the mixture was washed with hexanes (3 ×), then quenched
with a 10% aq NaHSO4 solution (5 mL) and extracted with EtOAc.
The combined organic phases were washed with brine, and dried
over MgSO4. Concentration afforded cleanly a mixture of the
mono-alkylation and bis-alkylation products as a clear oil (0.35 g,
84%, 8.4:1 ratio).
(d, JPCCC = 7.5 Hz), 128.1 (d, JPCCCC = 3.8 Hz), 129.2 (d, JPCCCCC
=
3.7 Hz), 130.8 (d, JPCC = 7.8 Hz), 132.1 (d, JPCCC = 5.7 Hz), 133.2
(d, JPCCCC = 3.4 Hz).
31P NMR (121.47 MHz, CDCl3): d = 34.6 (dm, JPH = 552 Hz).
HRMS (EI+): m/z calcd for C11H16O2BrP: 291.0150; found:
291.0153.
Ethyl Butyl-H-phosphinate11c,22,24 (Table 1, Entry 6)
Yield: 22%; RN: [21661-52-9].
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7 Hz, 3 H), 1.37 (t,
J = 7 Hz, 3 H), 1.38–1.66, 1.73–1.83 (m, 6 H), 4.04–4.24 (m, 2 H),
7.08 (d, JHP = 526 Hz, 1 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 16.5 (d, JPOCC = 6
Hz), 22.9 (d, JPCC = 3.2 Hz, CH2), 23.8 (d, JPOC = 16 Hz), 28.6 (d,
JPC = 94 Hz), 32.2, 32.6 (d, JPCC = 6 Hz), 62.5 (d, JPOC = 6.9 Hz).
Mono-Alkylation Product
1H NMR (300 MHz, CDCl3): d = 1.37 (t, J = 7 Hz, 3 H), 2.67 (dd,
J = 8, 19 Hz, 2 H), 4.1–4.5 (m, 2 H), 5.3–5.4 (m, 2 H), 5.65–5.85
(m, 1 H), 7.02 (dt, JHP = 543 Hz, J = 2 Hz, 1 H).
31P NMR (121.47 MHz, CDCl3): d = 37.26 (dm, JPH = 543 Hz, 89%,
mono-alkylation product), 50.42 (11%, bis-alkylation product16a).
31P NMR (121.47 MHz, CDCl3): d = 40.26 (dm, JPH = 526 Hz).
Butyl Benzyl-H-phosphinate10,11c (Table 1, Entry 2)
Yield: 70%; RN: [115049-29-1].
Butyl Butyl-H-phosphinate (Table 1, Entry 7)
Yield: 51%; RN: [21661-55-2].
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.3 Hz, 3 H), 1.30
(sext, J = 7.3 Hz, 2 H), 1.57–1.67 (m, 2 H), 3.19 (dd, JHP = 18.6 Hz,
J = 2 Hz, 2 H), 3.94, 4.08 (tdd, JHP = 6.4 Hz, J = 8.5, 10 Hz, 2 H),
7.03 (dt, JHP = 544 Hz, J = 1.8 Hz, 1 H), 7.21–7.37 (m, 5 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 18.9, 32.6, 37.2 (d,
JPC = 89 Hz), 66.9 (d, JPOC = 7.5 Hz), 127.4 (d, JPCCCCC = 3.8 Hz),
129.1 (d, JPCCCC = 3.2 Hz), 130.0 (d, JPCCC = 6.6 Hz), 130.1 (d,
JPCC = 7.2 Hz).
1H NMR (300 MHz, CDCl3): d = 0.91–0.97 (m, 6 H), 1.26–1.83 (m,
10 H), 3.93–4.17 (m, 2 H), 7.08 (d, JHP = 529 Hz, 1 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 18.99, 22.9 (d,
JPCC = 3.2 Hz), 23.8 (d, JPOC = 16 Hz), 28.6 (d, JPC = 93 Hz), 32.6
(d, JPCC = 6 Hz), 66.4 (d, JPOC = 7 Hz).
31P NMR (121.47 MHz, CDCl3): d = 40.95 (dm, JPH = 529 Hz).
HRMS (EI+): m/z calcd for C8H19O2P: 179.1201; found: 179.1201.
31P NMR (121.47 MHz, CDCl3): d = 38.01 (dm, JPH = 544 Hz).
HRMS (EI+): m/z calcd for C11H17O2P: 212.0966; found: 212.0966.
Butyl Octyl-H-phosphinate9 (Table 1, Entry 9)
Yield: 35%; ref.9a
Isopropyl Benzyl-H-phosphinate1 (Table 1, Entry 3)
Yield: 65%.
1H NMR (300 MHz, CDCl3): d = 1.24, 1.33 (2 × d, J = 6.2 Hz, 6 H),
3.20 (dd, JHP = 17.9 Hz, J = 1.8 Hz, 2 H), 4.55–4.63 (m, 1 H), 7.06
(dt, JHP = 541 Hz, J = 2 Hz, 1 H ), 7.23–7.33 (m, 5 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 23.5, 24.4 (2 × d, JPOCC
4.3 Hz), 37.5 (d, JPC = 89 Hz), 71.9 (d, JPOC = 6 Hz), 127.4 (d,
JPCCCCC = 4.4 Hz), 129.0 (d, JPCCCC = 3.2 Hz), 130.0 (d, JPCCC = 6.3
Hz), 130.1 (d, JPCC = 7.2 Hz).
31P NMR (121.47 MHz, CDCl3): d = 35.10 (dm, JPH = 541 Hz).
HRMS (EI+): m/z calcd for C10H15O2P: 198.0816; found: 198.0810.
1H NMR (300 MHz, CDCl3): d = 0.85 (t, J = 6.7 Hz, 3 H), 0.94 (t,
J = 7.3 Hz, 3 H), 1.20–1.82 (m, 18 H), 3.98, 4.11 (tdd, JHP = 6.5 Hz,
J = 8.5, 10 Hz, 2 H), 7.03 (dt, JHP = 526 Hz, J = 1.7 Hz, 1 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.4, 13.9, 18.6, 20.5,
20.6, 22.4, 28.6 (d, JPC = 93 Hz), 30.6 (d, JPOC = 16 Hz), 32.2, 32.6
(d, JPCC = 6 Hz), 65.9 (d, JPOC = 7 Hz).
31P NMR (121.47 MHz, CDCl3): d = 40.78 (dm, JPH = 526 Hz).
HRMS (EI+): m/z calcd for C12H27O2P: 235.1827; found: 235.1829.
=
Butyl Methyl-H-phosphinate12d,e (Table 1, Entry 11)
Yield: 82%; RN: [6172-80-1].
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.6 Hz, 3 H), 1.44
(sext, J = 7.4 Hz, 2 H), 1.63 (dd, JHP = 16 Hz, J = 1.8 Hz, 3 H), 1.69–
1.75 (m, 2 H), 3.94–4.22 (m, 2 H), 7.48 (d, JHP = 547 Hz, 1 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 15.2 (d, JPC = 94
Hz), 18.9, 32.6 (d, JPCC = 6.7 Hz), 66.9 (d, JPOC = 7.5 Hz).
Benzyl Benzyl-H-phosphinate (Table 1, Entry 4)
Yield: 45%.
1H NMR (300 MHz, CDCl3): d = 3.24 (dd, JHP = 19 Hz, J = 1.5 Hz,
2 H), 5.01, 5.12 (ABX system, JAB = 11.8 Hz, JAX = 10.2 Hz, JBX
=
8.5 Hz, 2 H), 7.09 (dt, JHP = 548 Hz, J = 1.5 Hz, 1 H), 7.21–7.39 (m,
10 H).
31P NMR (121.47 MHz, CDCl3): d = 40.13 (dm, JPH = 547 Hz).
HRMS (EI+): m/z calcd for C5H13O2P: 137.0731; found: 137.0726.
13C {1H} NMR (75.45 MHz, CDCl3): d = 37.2 (d, JPC = 88 Hz), 68.1
(d, JPOC = 6.6 Hz), 127.2, 127.6 (d, JPCCCCC = 3.8 Hz), 128.2, 128.8,
128.9, 129.2 (d, JPCCCC = 3.2 Hz), 130.0 (d, JPCCC = 6.6 Hz), 130.1
(d, JPCC = 7.2 Hz).
Butyl Allyl-H-phosphinate25 (Table 1, Entry 13)
Yield: 71%.
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.6 Hz, 3 H), 1.42
(sext, J = 7.6 Hz, 2 H), 1.64–1.74 (m, 2 H), 2.66 (ddd, JHP = 19 Hz,
J = 1.7, 7.5 Hz, 2 H), 4.03, 4.13 (tdd, JHP = 6.7 Hz, J = 8.5, 9.5 Hz,
31P NMR (121.47 MHz, CDCl3): d = 37.73 (dm, JPH = 548 Hz).
Butyl (2-Bromobenzyl)-H-phosphinate (Table 1, Entry 5)
Yield: 76%.
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330
I. Abrunhosa-Thomas et al.
PAPER
2 H), 5.25–5.82 (m, 2 H), 5.68–5.82 (m, 1 H), 7.00 (td, JHP = 543
Hz, J = 2 Hz, 1 H).
7.2 Hz), 110.6 (d, JPCC = 9.2 Hz), 123.9. 124.5, 131.6, 135.7, 142.2
(d, JPCCC = 14.0 Hz).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 18.9, 32.6 (d,
JPOCC = 5.8 Hz), 35.0 (d, JPC = 90.4 Hz), 66.5 (d, JPOC = 7.5 Hz),
121.5 (d, JPCCC = 13.8 Hz), 125.9 (d, JPCC = 9.2 Hz).
31P NMR (121.47 MHz, CDCl3): d = 38.36 (dm, JPH = 537 Hz).
HRMS (EI+): m/z calcd for C19H35O2P: 326.2375; found: 326.2374.
31P NMR (121.47 MHz, CDCl3): d = 37.69 (dm, JPH = 543 Hz).
HRMS (EI+): m/z calcd for C7H15O2P: 163.0888; found: 163.0883.
(E,E)-3-[Butoxy(3,7,11-trimethyl-2,6,10-dodecatrienyl)phos-
phinyl]propanoic Acid Benzyl Ester (5) (Scheme 2)
To a mixture of benzyl acrylate (0.0348 g, 1 equiv, 0.214 mmol) and
butyl farnesyl-H-phosphinate (4; 0.07 g, 1 equiv, 0.214 mmol) in
CH2Cl2 (0.5 mL) was added BSA (0.053 mL, 1 equiv, 0.214 mmol),
dropwise at r.t. After stirring at r.t. for 14 h, the reaction mixture was
quenched with a solution of NaHSO4 (0.5 mL, 20% in water) and
extracted with EtOAc (3 ×). The combined organic phases were
washed with brine, then dried over MgSO4 and concentrated under
vacuum. The crude oil obtained was purified by chromatography
over silica gel (hexane–EtOAc, 80:20) to produce compound 5
(0.048 g, 49%) as a yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H), 1.51
(sext, J = 7.3 Hz, 2 H), 1.53–1.69 (m, 14 H), 1.91–2.11 (m, 10 H),
2.49–2.71 (m, 4 H), 3.93–4.03 (m, 2 H), 5.05–5.11 (m, 2 H), 5.12
(s, 2 H), 5.13–5.23 (m, 1 H), 7.32–7.41 (m, 5 H).
Benzyl Allyl-H-phosphinate (Table 1, Entry 14)
Yield: 39%.
1H NMR (300 MHz, CDCl3): d = 2.66 (dd, JHP = 18 Hz, J = 7.3 Hz,
2 H), 5.03, 5.15 (ABX system, JAB = 11.7 Hz, JAX = 9.4 Hz, JBX
=
10.3 Hz, 2 H), 5.20–5.33 (m, 1 H), 5.65–5.81 (m, 2 H), 7.04 (dtd,
JHP = 549 Hz, J = 0.9, 2.3 Hz, 1 H), 7.34–7.51 (m, 5 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 34.9 (d, JPC = 90 Hz), 67.9
(d, JPOC = 6.6 Hz), 121.8 (d, JPCCC = 13.8 Hz), 125.6 (d, JPCC = 9.5
Hz), 128.3, 128.9, 129.0, 135.8 (d, JPOCC = 5.5 Hz).
31P NMR (121.47, CDCl3): d = 37.54 (dm, JPH = 549 Hz).
HRMS (EI+): m/z calcd for C10H13O2P: 196.0653; found: 196.0654.
13C {1H} NMR (22.63 MHz, CDCl3): d = 13.3, 15.7, 16.2 (d,
JPCCCC = 2.2 Hz), 17.4, 18.5, 23.4 (d, JPC = 93 Hz), 25.4, 26.1 (d,
JPCCCCC = 3.2 Hz), 26.4, 26.5, 28.9 (d, JPC = 89.5 Hz), 32.4 (d,
Butyl Cinnamyl-H-phosphinate (Table 1, Entry 16)
Yield: 60%.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.6 Hz, 3 H), 1.42
(sext, J = 7.6 Hz, 2 H), 1.65–1.74 (m, 2 H), 2.66 (dd, J = 7.6 Hz,
JHP = 19 Hz, 2 H), 4.03, 4.13 (tdd, JHP = 6.5 Hz, J = 8.5, 10.2 Hz, 2
H), 6.03–6.16 (m, 1 H), 6.54 (dd, J = 5.9, 15.8 Hz, 1 H), 7.04 (td,
JHP = 543 Hz, J = 1.7 Hz, 1 H), 7.27–7.37 (m, 5 H).
JPOCC = 5.6 Hz), 39.4, 64.0 (d, JPOC = 6.9 Hz), 66.4, 112.2 (d, JPCC
=
8.7 Hz), 123.0, 123.4, 127.9, 128.0, 128.3, 130.9, 135.4, 140.4 (d,
JPCCC = 12.8 Hz), 171.5.
31P NMR (121.47 MHz, CDCl3): d = 53.91 (s).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 19.0, 32.6 (d,
JPOCC = 5.7 Hz), 34.3 (d, JPC = 90.4 Hz), 66.6 (d, JPOC = 7.5 Hz),
116.9 (d, JPCC = 10.1 Hz), 126.5 (d, JPCCCCC = 2.3 Hz), 128.1, 128.8,
136.1 (d, JPCCCC = 4.3 Hz), 136.6 (d, JPCCC = 14.4 Hz).
31P NMR (121.47 MHz, CDCl3): d = 37.28 (dm, JPH = 543 Hz).
HRMS (EI+): m/z calcd for C13H19O2P: 238.1123; found: 238.1122.
Butyl (3-Methylbut-2-en-1-yl)-H-phosphinate (Table 1, Entry
19)
Yield: 81%.
1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.6 Hz, 3 H), 1.40
(sext, J = 7.6 Hz, 2 H), 1.59 (s, 3 H), 1.65–1.78 (m, 8 H), 2.55–2.66
(m, 2 H), 3.98–4.16 (m, 2 H), 5.07–5.16 (m, 1 H), 7.04 (dm, JHP
=
535, 1 H).
Butyl Geranyl-H-phosphinate (Table 1, Entry 17)
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 18.1 (d, JPCCCC = 3.5
Hz), 18.7, 26.0 (d, JPCCCC = 3.5 Hz), 29.8 (d, JPC = 91.8 Hz), 32.7 (d,
JPOCC = 6 Hz), 66.4 (d, JPOC = 7.5 Hz), 110.7 (d, JPCC = 9.2 Hz),
138.3 (d, JPCCC = 14.4 Hz).
31P NMR (121.47 MHz, CDCl3): d = 37.99 (dm, JPH = 535 Hz).
HRMS (EI+): m/z calcd for C9H19O2P: 190.1123; found: 190.1127.
Yield: 62%.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H), 1.51
(sext, J = 7.3 Hz, 2 H), 1.60 (s, 3 H), 1.63–1.75 (m, 9 H), 2.08 (s, 3
H), 2.55–2.66 (m, 2 H), 3.98, 4.10 (tdd, JHP = 6.7 Hz, J = 8.5, 10.0
Hz, 2 H), 5.04–5.15 (m, 2 H), 7.04 (ddd, JHP = 537 Hz, J = 2.6 Hz,
J = 1.5 Hz, 1 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 16.7 (d, JPCCCC = 3.2
Hz), 17.9, 19.0, 25.9, 26.6 (d, JPCCCCC = 3.7 Hz), 30.2 (d, JPC = 94
Hz), 32.6 (d, JPOCC = 6 Hz), 39.9 (d, JPCCCC = 3.5 Hz), 66.6 (d,
JPOC = 7.2 Hz), 110.6 (d, JPCC = 8.9 Hz), 123.9. 132.0, 142.2 (d,
JPCCC = 14.1 Hz).
Acknowledgment
The National Institute of General Medical Sciences/NIH (1R01
GM067610) is gratefully acknowledged for financial support.
31P NMR (121.47 MHz, CDCl3): d = 38.4 (dm, JPH = 537 Hz).
HRMS (EI+): m/z calcd for C14H27O2P: 258.1749; found: 258.1747.
References
(1) Gallagher, M. J.; Ranasinghe, M. G.; Jenkins, I. D.
Phosphorus, Sulfur Silicon Relat. Elem. 1996, 115, 255.
(2) (a) Gallagher, M. J.; Sussman, J. Phosphorus 1975, 5, 91.
(b) Maier, L. Helv. Chim. Acta 1973, 56, 489.
(c) Wroblewski, A. E.; Verkade, J. G. J. Am. Chem. Soc.
1996, 118, 10168. (d) See also reference 6.
(3) (a) Fookes, C. J. R.; Gallagher, M. J. J. Chem. Soc., Perkin
Trans. 1 1975, 1876. (b) Fookes, C. J. R.; Gallagher, M. J.;
Honneger, H. J. Chem. Soc., Chem. Commun. 1978, 324.
(4) Nifant’ev, E. E.; Levitan, L. P. J. Gen. Chem. USSR (Engl.
Transl.) 1965, 35, 762.
Butyl Farnesyl-H-phosphinate (4) (Scheme 2, Table 1, Entry 18)
Yield: 80%.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7.3 Hz, 3 H), 1.51
(sext, J = 7.3 Hz, 2 H), 1.59 (s, 3 H), 1.63–1.75 (m, 11 H), 1.94–2.13
(m, 8 H), 2.55–2.66 (m, 2 H), 3.98, 4.10 (tdd, JHP = 6.5 Hz, J = 8.5,
10.2 Hz, 2 H), 5.05–5.16 (m, 3 H), 7.04 (ddd, JHP = 537 Hz, J = 1.5,
2.6 Hz, 1 H).
13C {1H} NMR (75.45 MHz, CDCl3): d = 13.8, 16.2, 16.8 (d,
JPCCCC = 3.2 Hz), 17.9, 19.0, 25.9, 26.6 (d, JPCCCCC = 3.7 Hz), 26.9,
30.2 (d, JPC = 91.6 Hz), 32.6 (d, JPOCC = 6 Hz), 39.9, 66.6 (d, JPOC
=
Synthesis 2006, No. 2, 325–331 © Thieme Stuttgart · New York

PAPER
(5) (a) Dingwall, J. G.; Ehrenfreund, J.; Hall, R. G.; Jack, J.
Direct Monoalkylation of Alkyl Phosphinates
331
(17) (a) Patel, D. V.; Gordon, E. M.; Schmidt, R. J.; Weller, H.
N.; Young, M. G.; Zahler, R.; Barbacid, M.; Carboni, J. M.;
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(18) For the conversion of RP(O)(OR¢)H into RP(O)(OR¢)Cl and
esterification, see for example: (a) Bartlett, P. A.;
Giangiordano, M. A. J. Org. Chem. 1996, 61, 3433.
(b) Mucha, A.; Kafarski, P.; Plenat, F.; Cristau, H.-J.
Tetrahedron 1994, 50, 12743.
Phosphorus Sulfur Relat. Elem. 1987, 30, 571.
(b) McCleery, P. P.; Tuck, B. J. Chem. Soc., Perkin Trans. 1
1989, 1319. (c) Dingwall, J. G.; Ehrenfreund, J.; Hall, R. G.
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(6) Deprèle, S.; Montchamp, J.-L. J. Organomet. Chem. 2002,
(19) Based on this NMR data, it is not possible to unambiguously
distinguish between the anion and the proposed hydrogen-
bonded or tight ion-pair structures [for example for
phosphites, (RO)3P and (RO)2PO– appear in the same range
of chemical shift (d = 130–150 ppm in 31P NMR), though
there too ion-pairs are possible]: (a) Galkin, V. I.;
Khabibullina, A. B.; Smirnov, V. N.; Cherkasov, R. A.;
Pudovik, A. N. Dokl. Chem. (Engl. Transl.) 1987, 292, 21.
(b) Moedritzer, K. J. Inorg. Nucl. Chem. 1961, 22, 19.
However, it is not likely that DBU is sufficiently basic to
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compounds have been characterized, for example:
(c) (MeO)2PH [d = 171 (JP–H = 203 Hz)]: Centofanti, L. F.
Inorg. Chem. 1973, 12, 1131. (d) (i-BuO)2PH [d = 163
(JP–H = 200 Hz)]: Lutsenko, I. F.; Proskurnina, M. V.;
Borisenko, A. A. Dokl. Chem. (Engl. Transl.) 1970, 193,
553. (e) (NeoO)2PH [d = 162 (JP–H = 198 Hz)]: Stec, W.;
Uznanski, B.; Houalla, D.; Wolf, R. C. R. Acad. Sci. Ser. C
1975, 281, 727. (f) (EtO)P(OTMS)H [d = 154 (JP–H = 184
Hz)], (TMSO)2PH [d = 140 (JP–H = 176 Hz)]: Livantsov, M.
V.; Prishchenko, A. A.; Lutsenko, I. F. J. Gen. Chem. USSR
(Engl. Transl.) 1986, 56, 1976. (g) ROP(OR¢)H has been
proposed as a likely intermediate in the transesterification of
alkyl phosphinates but could not be detected: Gallagher, M.
J.; Honneger, H. J. Chem. Soc., Chem. Commun. 1978, 54.
(20) Review: Montchamp, J.-L. J. Organomet. Chem. 2005, 690,
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(21) (a) Montchamp, J.-L.; Dumond, Y. R. J. Am. Chem. Soc.
2001, 123, 510. (b) Anilinium hypophosphite is now also
commercially available from Aldrich.
(22) Froestl, W.; Mickel, S. J.; von Sprecher, G.; Diel, P. J.; Hall,
R. G.; Maier, L.; Strub, D.; Melillo, V.; Baumann, P. A.;
Bernasconi, R.; Gentsch, C.; Hauser, K.; Jaekel, J.; Karlsson,
G.; Klebs, K.; Maitre, L.; Marescaux, C.; Pozza, M. F.;
Schmutz, M.; Steinmann, M. W.; van Riezen, H.; Vassout,
A.; Mondadori, C.; Olpe, H.-R.; Waldmeier, P. C.; Bittiger,
H. J. Med. Chem. 1995, 38, 3313.
(23) (a) Yamagishi, T.; Kusano, T.; Yokomatsu, T.; Shibuya, S.
Synlett 2002, 1471. (b) Yamagishi, T.; Kusano, T.;
Kaboudin, B.; Yokomatsu, T.; Sakuma, C.; Shibuya, S.
Tetrahedron 2003, 59, 767.
643-644, 154.
(7) For example: Ribière, P.; Bravo-Altamirano, K.; Antczak,
M.; Hawkins, J. D.; Montchamp, J.-L. J. Org. Chem. 2005,
70, 4064.
(8) The purification of H-phosphinate esters is often
complicated by the very polar nature of these compounds,
and their relative ease of hydrolysis. Benzyl alkyl-H-
phosphinate esters are more labile than other alkyl esters.
(9) (a) Deprèle, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66,
6745. (b) Deprèle, S.; Montchamp, J.-L. J. Am. Chem. Soc.
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(10) Bravo-Altamirano, K.; Huang, Z.; Montchamp, J.-L.
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Chang, C.-Y. Dokl. Chem. (Engl. Transl.) 1959, 125, 309.
(12) See for example: (a) [CH3P(O)(OEt)H, 81%]: Kehler, J.;
Ebert, B.; Dahl, O.; Krogsgaard-Larsen, P. Tetrahedron
1999, 55, 771. (b) [CH3P(O)(OEt)H, 88%]: Renard, P.-Y.;
Vayron, P.; Taran, F.; Miokowski, C. Tetrahedron Lett.
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V. I.; Abramov, V. S. J. Gen. Chem. USSR (Engl. Transl.)
1965, 35, 2215. (d) [CH3P(O)(OAlk)H, 60–75%]: Gruzdev,
V. G.; Karavanov, K. V.; Ivin, S. V. J. Gen. Chem. USSR
(Engl. Transl.) 1968, 38, 1499. (e) [CH3P(O)(OBu)H,
68%]: Gladshtein, B. M.; Shitov, L. N. J. Gen. Chem. USSR
(Engl. Transl.) 1969, 39, 1913. (f) Murata, Y.; Woodward,
R. M.; Miledi, R.; Overman, L. E. Bioorg. Med. Chem. Lett.
1996, 6, 2073.
(13) Kehler, J.; Ebert, B.; Dahl, O.; Krogsgaard-Larsen, P. J.
Chem. Soc., Perkin Trans. 1 1998, 3241.
(14) We thank Jakob Heid, Klemens Kaupmann, and Wolfgang
Froestl (Novartis Pharma) for conducting the GTPgammaS
binding assay.
(15) Boyd, E. A.; Regan, A. C.; James, K. Tetrahedron Lett.
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(16) (a) Bujard, M.; Gouverneur, V.; Mioskowski, C. J. Org.
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(24) Petnehazy, I.; Jaszay, Z. M.; Szabo, A.; Everaert, K. Synth.
Commun. 2003, 33, 1665.
(25) Kabachnik, M. I.; Chang, J.-Y.; Tsvetkov, E. N. J. Gen.
Chem. USSR (Engl. Transl.) 1962, 32, 3351.
Synthesis 2006, No. 2, 325–331 © Thieme Stuttgart · New York