Alkylation of H-phosphinate esters under basic conditions

Article abstract of DOI:10.1021/jo062436o

(Chemical Equation Presented) An efficient and general procedure was developed for the direct alkylation of H-phosphinate esters with LHMDS at low temperature. The simplicity of the reaction allows the use of various H-phosphinate esters and takes place with a wide range of electrophiles. The approach can be employed to access some GABA analogues or precursors to GABA analogues. The isolated yields are moderate to good. This is the first report of an alkylation with a secondary iodide or a primary chloride.

Full text of DOI:10.1021/jo062436o

Alkylation of H-Phosphinate Esters under Basic Conditions
Isabelle Abrunhosa-Thomas, Claire E. Sellers, and Jean-Luc Montchamp*
Department of Chemistry, Texas Christian UniVersity, TCU Box 298860, Fort Worth, Texas 76129
j.montchamp@tcu.edu
ReceiVed NoVember 27, 2006
An efficient and general procedure was developed for the direct alkylation of H-phosphinate esters with
LHMDS at low temperature. The simplicity of the reaction allows the use of various H-phosphinate
esters and takes place with a wide range of electrophiles. The approach can be employed to access some
GABA analogues or precursors to GABA analogues. The isolated yields are moderate to good. This is
the first report of an alkylation with a secondary iodide or a primary chloride.
Introduction
Over the years, many examples of base-promoted H-phos-
phinate alkylation (eq 1) have been reported in the literature.1
However, there does not appear to be a standard set of
conditions, and surprisingly, we have not found any general
study of this reaction. Various bases (RONa, NaH, BuLi, LDA,
KHMDS) and stoichiometries have been employed.1 A some-
what more widely employed approach (eq 2) consists of
* To whom correspondence should be addressed. Fax: (+1) 817 257 5851.
Phone: (+1) 817 257 6201.
(1) Base-promoted alkylations of H-phosphinate esters: (a) Baillie, A.
C.; Cornell, C. L.; Wright, B. J.; Wright, K. Tetrahedron Lett. 1992, 33,
5133 (NaH). (b) Baylis, E. K. Tetrahedron Lett. 1995, 36, 9385 (Na). (c)
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 (NaH, BuLi). (d) Froestl, W.; Mickel, S. J.; Hall, R.
G.; von Sprecher, G.; Diel, P. J.; Strub, D.; Baumann, P. A.; Brugger, F.;
Gentsch, C.; Jaekel, J.; Olpe, H.-R.; Rihs, G.; Vassout, A.; Waldmeier, P.
C.; Bittiger, H. J. Med. Chem. 1995, 38, 3297. (NaH); (e) Magnin, D. R.;
Biller, S. A.; Dickson, J. K., Jr.; Logan, J. V.; Lawrence, R. M.; Chen, Y.;
Sulsky, R. B.; Ciosek, C. P., Jr.; Harrity, T. W.; Jolibois, K. G.; Kunselman,
L. K.; Rich, L. C.; Slusarchyk, D. A. J. Med. Chem. 1995, 38, 2596
(NaHMDS). (f) Gallagher, M. J.; Ranasinghe, M. G.; Jenkins, I. D.
Phosphorus, Sulfur Silicon Relat. Elem. 1996, 115, 255 (i-PrONa). (g)
Fairhurst, R. A.; Collingwood, S. P.; Lambert, D.; Taylor, R. J. Synlett
2001, 467 (KHMDS). (h) Larenco, C.; Villien, L.; Kaufmann, G. Tetra-
hedron 1984, 40, 2731 (NaH). (i) McKittrick, B. A.; Stamford, A. W.; Weng,
X.; Ma, K.; Chackalamannil, S.; Czarniecki, M.; Cleven, R. M.; Fawzi, A.
B. Bioorg. Med. Chem. Lett. 1996, 6, 1629 (NaH, LDA) (j) Froestl, W.;
Bettler, B.; Bittiger, H.; Heid, J.; Kaupmann, K.; Mickel, S. J.; Strub, D.
Farmaco 2003, 58, 173 (NaH). (k) Kehler, J.; Ebert, B.; Dahl, O.;
Krogsgaard-Larsen, P. Tetrahedron 1999, 55, 771 (LDA, t-BuOK). (l)
Hemmi, K.; Takeno, H.; Hashimoto, M.; Kamiya, T. Chem. Pharm. Bull.
1982, 30, 111 (BuLi). (m) Lindell, S. D.; Turner, R. M. Tetrahedron Lett.
1990, 31, 5381 (NaH). (n) Gallagher, M. J.; Honegger, H. Tetrahedron
Lett. 1977, 2987 (MeONa). (o) Hall, R. G.; Kane, P. D.; Bittiger, H.; Froestl,
W. J. Labelled Compd. Radiopharm. 1995, 129.
silylating H-phosphinic acids followed by an Arbuzov-like
reaction with alkyl halides.2 This method also has its limitations,
and it often requires esterification of the dialkylphosphinic acid
products when further manipulations are desired.
Functionalized, differentially substituted phosphinate esters
R1R2P(O)(OR) are important organophosphorus intermediates,
particularly in the synthesis of medicinally relevant protease
inhibitors and ATP-dependent ligases.3 Over the past few years,
our laboratory has been developing various approaches to
prepare H-phosphinic acids and esters.4 With these compounds
becoming more widely available, we are turning our focus to
(2) For some representative examples of the silicon method: (a) Boyd,
E. A.; Regan, A. C.; James, K. Tetrahedron Lett. 1994, 35, 4223. (b) Boyd,
E. A.; Corless, M.; James, K.; Regan, A. C. Tetrahedron Lett. 1990, 31,
2933. (c) Malachowski, W. P.; Coward, J. K. J. Org. Chem. 1994, 59, 7625.
(d) Reck, F.; Marmor, S.; Fisher, S.; Wuonola, M. A. Bioorg. Med. Chem.
Lett. 2001, 11, 1451. (e) Ribie`re, P.; Altamirano-Bravo, K.; Antczak, M.
I.; Hawkins, J. D.; Montchamp, J.-L. J. Org. Chem. 2005, 70, 4064. See
also refs 1c, 1d, and 1h.
10.1021/jo062436o CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/13/2007
J. Org. Chem. 2007, 72, 2851-2856
2851

Abrunhosa-Thomas et al.
TABLE 1. Role of the Base in the Alkylation of Butyl
TABLE 2. Role of the Electrophile in the Alkylation of
PhP(O)(OEt)H with LHMDS
Octyl-H-phosphinate with Butyl Iodidea
NMR
isolated
yield
NMR
conversion
conversion
b
c
entry
RX
deoxygenationa
temperature
%
%
b
entry
substrate
conditions
base
Na
i-PrMgCl
MeLi
BuLi
LDA
%
1
2
3
4
5
6
7
8
CH3I
OctI
no
no
no
yes
no
yes
yes
yes
-78 °C to rt
100
100
80
92
1
77
88
87
98
80
57
71
1
2
3
4
5
6
BuI
BuI
BuI
BuI
BuI
BuI
THF, 0 °C to rt
16
64
56
60
89
-78 °C to rt
THF, -78 °C to rt
THF, -78 °C to rt
THF, -78 °C to rt
THF, -78 °C to rt
THF, -78 °C to rt
OctBr
OctBr
OctCl
OctCl
OctOTs
i-PrI
-78 °C to rt
-78 °C to rt
-78 °C to reflux
-78 °C to reflux
-78 °C to reflux
-78 °C to reflux
51
62
45
LHMDS
100
a All reactions were conducted in freshly distilled anhydrous THF and
under N2. b NMR conversion yields are determined by integration of all
the resonances in the crude 31P NMR spectra.
a Deoxygenation was conducted by placing a THF solution of the
H-phosphinate under vacuum at -78 °C for 5 min and then adding N2.
b NMR conversion yields are determined by integration of all the resonances
in the 31P NMR spectra. c Isolated yield of pure compounds after chroma-
tography on silica gel.
the functionalization of these intermediates with the formation
of a second phosphorus-carbon bond. Our literature survey
uncovered the lack of general conditions for the base-promoted
alkylation of H-phosphinates with alkyl halides. Therefore, we
decided to investigate the scope and limitations of this trans-
formation. Herein, we report a detailed investigation which led
to a standardized set of conditions allowing the preparation of
functionalized dialkylphosphinates.
is observed as the reactivity of the electrophile decreases. 31P
NMR analysis of these reaction mixtures indicates the formation
of PhP(O)(OEt)OLi (δ 17.2 ppm), along with the P(III) anion
PhP(OEt)(OLi) (δ 149 ppm), and the alkylation product
PhP(O)(OEt)Oct (δ 44.8 ppm). The low reactivity of the
electrophile requires heating the reaction mixture during which
competitive oxidation of the anion takes place, so a deoxygen-
ation protocol was investigated.5 Instead of a rigorous freeze-
thaw-degas cycle, we opted for a simpler, more practical,
deoxygenation method consisting of placing the reaction flask
containing the H-phosphinate ester and THF under vacuum for
5 min at -78 °C and filling it with nitrogen prior to adding the
other reagents. This moderate deoxygenation is sufficient to
provide good alkylation yields with unreactive electrophiles
(X ) Cl, OTs). To the best of our knowledge, this is the first
example of successful alkylation with an alkyl chloride. Unlike
primary iodides, which are sufficiently reactive to not necessitate
deoxygenation, isopropyl iodide behaves like n-octyl chloride
and tosylate. This is also the first time a secondary halide is
employed in the alkylation of a H-phosphinate.
The next stage in this study was to investigate the scope with
respect to both the H-phosphinate starting material and the
electrophile (Table 3).
As shown in Table 3, the general conditions can be success-
fully applied to a range of H-phosphinate/electrophile pairs. The
alkylation of the “Ciba-Geigy reagent”, (CH3C(OEt)2P(O)-
(OEt)H),6 was examined in some detail (entries 1-9), in part
because it is a representative H-phosphinate ester but also
because the ketal group can be cleaved to unmask a P(O)H
functional group (eq 3).7 While we8 and Gallagher9 have
Results and Discussion
Butyl octyl-H-phosphinate was selected as a test substrate to
determine the choice of base, with n-butyl iodide as the
electrophile (Table 1). The phosphorus nucleophile, butyl iodide,
and base were used in equimolar quantities, and the results were
studied by 31P NMR of the crude reaction mixtures. Although
alkylation takes place in all cases, significant differences are
observed. Not surprisingly, nucleophilic bases, such as MeLi
and BuLi (entries 3 and 4), give lower yields due to the
competing direct substitution of the butyl ester to form a
secondary phosphine oxide, whereas the strong non-nucleophilic
bases (entries 5 and 6) give better results. After this initial
screening, LHMDS was selected to investigate the influence of
the electrophile.
Table 2 summarizes the results obtained in the LHMDS-
mediated alkylation of PhP(O)(OEt)H with various alkyl halides.
Under otherwise identical conditions, a clear erosion in yield
(3) Representative examples: (a) Grembecka, J.; Mucha, A.; Cierpicki,
T.; Kafarski, P. J. Med. Chem. 2003, 46, 2641. (b) Lloyd, J.; Schmidt, J.
B.; Hunt, J. T.; Barrish, J. C.; Little, D. K.; Tymiak, A. A. Bioorg. Med.
Chem. Lett. 1996, 6, 1323. (c) Karanewsky, D. S.; Badia, M. C.; Cushman,
D. W.; DeForrest, J. M.; Dejneka, T.; Loots, M. J.; Perri, M. G.; Petrillo,
E. W., Jr.; Powell, J. R. J. Med. Chem. 1988, 31, 204. (d) Qiao, L.; Nan,
F.; Kunkel, M.; Gallegos, A.; Powis, G.; Kozikowski, A. P. J. Med. Chem.
1998, 41, 3303. (e) Tokutake, N.; Hiratake, J.; Katoh, M.; Irie, T.; Kato,
H.; Oda, J. Bioorg. Med. Chem. 1998, 6, 1935. (f) Manthey, M. K.; Huang,
D. T. C.; Bubb, W. A.; Christopherson, R. I. J. Med. Chem. 1998, 41, 4550.
(g) Ebetino, F. H.; Berk, J. D. J. Organomet. Chem. 1997, 529, 135. (h)
Vayron, P.; Renard, P.-Y.; Valleix, A.; Mioskowski, C. Chem.sEur. J. 2000,
6, 1050. (i) Jackson, P. F.; Cole, D. C.; Slusher, B. S.; Stetz, S. L.; Ross,
L. E.; Donzati, B. A.; Trainor, D. A. J. Med. Chem. 1996, 39, 619. (j)
Hiratake, J. Chem. Rec. 2005, 5, 209. (k) Bartley, D. M.; Coward, J. K. J.
Org. Chem. 2005, 70, 6757. (l) Valiaeva, N.; Bartley, D.; Konno, T.;
Coward, J. K. J. Org. Chem. 2001, 66, 5146. (m) Jackson, P. F.; Tays, K.
L.; Maclin, K. M.; Ko, Y.-S.; Li, W.; Vitharana, D.; Tsukamoto, T.;
Stoermer, D.; Lu, X.-C. M.; Wozniak, K.; Slusher, B. S. J. Med. Chem.
2001, 44, 4170. (n) Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7,
629. (o) Flohr, A.; Aemissegger, A.; Hilvert, D. J. Med. Chem. 1999, 42,
2633. (p) Chen, S.; Coward, J. K. J. Org. Chem. 1998, 63, 502. (q) Hiratake,
J.; Kato, H.; Oda, J. J. Am. Chem. Soc. 1994, 116, 12059.
reported the direct alkylation of phosphinates ROP(O)H2 under
basic conditions which would provide the H-phosphinate esters
in one step (eq 4). The scope of this reaction is limited to
(5) Other workers have used deoxygenation previously (see ref 1k).
(6) For applications of the “Ciba-Geigy reagents”, see:(a) Dingwall, J.
G.; Ehrenfreund, J.; Hall, R. G.; Jack, J. 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. Tetrahedron
1989, 45, 3787. (d) Baylis, E. K. Tetrahedron Lett. 1995, 36, 9385. (e)
Baylis, E. K. Tetrahedron Lett. 1995, 36, 9389. (f) Bennett, S. N. L.; Hall,
R. G. J. Chem. Soc., Perkin Trans. 1 1995, 1145. See also refs 1c and 1d.
(4) Reviews: (a) Montchamp, J.-L. J. Organomet. Chem. 2005, 690,
2388. (b) Montchamp, J.-L. Spec. Chem. Mag. 2006, 26, 44.
2852 J. Org. Chem., Vol. 72, No. 8, 2007

Alkylation of H-Phosphinate Esters
TABLE 3. Reaction Scopea
a Details are provided in the Experimental Section. b Electrophiles that did not react successfully under a variety of conditions (excess of base, heating)
include CH2I2, (CH2Br)2, bromoacetates, and (EtO)2P(O)CF2Br. The reasons for failure are unclear. c Isolated yield of pure compounds after chromatography
on silica gel.
the base. With halomethylpyridine hydrohalides (Table 3, entries
6 and 15), an equivalent of LHMDS is employed prior to adding
the electrophile to the lithium phosphinate solution. The products
are precursors to GABA analogues, although none showed any
reactive electrophiles, such as allylic halides, and it fails with
significant activity on the GABA-B receptor after appropriate
most of the electrophiles used in Table 3.
deprotection steps.10
The H-phosphinate starting materials were generally available
Difluorochloromethane can be used to prepare the corre-
through our various methodologies (radical, Ni- and Pd-
sponding difluoromethylphosphinate. There was an example of
catalyzed hydrophosphinylations, or Pd-catalyzed cross-cou-
such a reaction in the literature, although the product was not
pling).4 Various functional groups (esters, imides, carbamates)
isolated.11 We have extended this to several substrates
are tolerated under the reaction conditions (Table 3). This
(Table 3, entries 9, 10, and 14). Our results concerning the
alkylation is comparable or superior to other conditions re-
reactivity of these compounds for the synthesis of fluorinated
ported,1 especially because it proceeds with equimolar amounts
phosphinates will be reported shortly.
of reagents. In the literature, an excess of reagent (electrophile
Epoxides also react satisfactorily in the presence of a
or H-phosphinate) is often employed.1 For example, the product
stoichiometric amount of boron trifluoride etherate (Scheme 1).
in Table 3, entry 2 was obtained in 42% yield using NaH as
Products 1 and 2 are obtained as nearly 1:1 mixtures of
(7) Cleavage of ketal protecting group to H-phosphinate: see ref 6.
(8) Abrunhosa-Thomas, I.; Ribie`re, P.; Adcock, A. C.; Montchamp, J.-
L. Synthesis 2006, 2, 325.
(9) Gallagher, M. J.; Ranasinghe, M. G.; Jenkins, I. D. Phosphorus, Sulfur
Silicon Relat. Elem. 1996, 115, 255.
(10) The compounds were inactive.
(11) CH3C(OEt)2P(O)(OEt)CF2H has been prepared in 95% yield using
NaH and was used in situ (see ref 1c). The synthetic use of this and other
difluorophosphinates described herein will be reported separately.
J. Org. Chem, Vol. 72, No. 8, 2007 2853

Abrunhosa-Thomas et al.
SCHEME 1. Epoxide Opening
A similar strategy could be applied for the preparation of
protected phosphinothricin (Scheme 4).17 The starting H-
phosphinate 9 was prepared using our recently disclosed
alkylation of phosphinate esters.8 The base-promoted alkylation
of 9 delivered protected phosphinothricin 10 in moderate yield.
Conclusion
Our investigations of the base-promoted alkylation of H-
phosphinate esters reveal that a standardized set of conditions
can be established, using LHMDS as the base and stoichiometric
amounts of the reagents. A moderate, yet practical, deoxygen-
ation protocol is necessary with less reactive electrophiles. A
wide variety of H-phosphinate esters can be alkylated, including
the first successful examples with a primary alkyl chloride
electrophile and a secondary alkyl iodide electrophile. The
reaction provides a viable alternative to the Arbuzov-like
silylation methodology, and it can be applied to the synthesis
of functionalized disubstituted phosphinate esters. The method
should be useful to phosphorus chemistry practitioners, par-
ticularly because the stoichiometry allows the use of valuable
moieties present both in the phosphorus nucleophile and in the
carbon electrophile.
SCHEME 2. Synthesis of the GABA-B Antagonist CGP
36742
Experimental Section
diastereoisomers because the phosphorus atom is stereogenic.
Although epoxide-openings have been reported using the
silylation approach, we could not find any report of this reaction
under basic conditions.12
Typical Alkylation Procedure. Neat alkyl H-phosphinate ester
(1.0 equiv, 1.5 mmol) was placed under vacuum in a dry two-neck
flask 10 min before use. Anhydrous THF (5 mL) was then added
under nitrogen. The flask was then placed at -78 °C and
deoxygenated under vacuum for 5 min. The reaction flask was back-
filled with nitrogen, and LHMDS (1.0 M in THF, 1.0 equiv,
1.5 mmol) was added at -78 °C. After 15 min, the electrophile
(1 equiv, 1.5 mmol) was added under N2 as a neat liquid or as a
0.5 M THF solution for solids. (In the case of the bromomethyl-
or chloromethylpyridine hydrobromide or -chloride, the pyridine
was first deprotonated at -78C in dry THF with LHMDS (1 equiv)
under N2 for 15 min and then added to the solution of the lithium
phosphinate.) After the addition of the electrophile, the temperature
of the solution was slowly allowed to warm to room temperature
(rt). (The temperature and reaction time after the solution reaches
rt depend on the reactivity of the electrophile.) Once at rt, the
reaction mixture was quenched with a saturated solution of
NH4Cl/brine, extracted with ethyl acetate (3×), dried over anhy-
drous MgSO4, and concentrated in vacuo. The resulting oil was
purified by column chromatography over silica gel.
Equation 5 shows an example of an intramolecular alkylation
to form P-heterocycle 3 (1-butoxy-phosphinane-1-oxide).
The based-promoted alkylation can be applied to the synthesis
of a variety of biologically active targets. For example, CGP
36742,1c,13 a GABA-B antagonist which is currently undergoing
phase II clinical trials, can be synthesized easily using our
radical-based hydrophosphinylation,14 followed by our alkox-
ysilane-based esterification to form 415 and the present alkylation
reaction to form intermediate 5 (see Scheme 2). Debenzylation
affords CGP 36742, 6, cleanly without the need for cumbersome
ion-exchange purification.
For the alkyl iodides and alkyl triflate, the mixture reacted for
10 min at rt, except for the hindered iodides that were refluxed for
6 h. The alkyl bromides were reacted for 2-4 h at rt. The alkyl
chlorides and tosylates were refluxed for 6 h or reacted at rt
Another example is shown in Scheme 3 for the rapid synthesis
of the known kynureninase inhibitor 8.16 The key step of forming
7 proceeds in good yield.
SCHEME 3. Synthesis of a Known Kynureninase Inhibitor
SCHEME 4. Synthesis of a Phosphinothricin Precursor
2854 J. Org. Chem., Vol. 72, No. 8, 2007

Alkylation of H-Phosphinate Esters
overnight (except for BOMCl, which reacted for 10 min at rt). For
HCF2Cl, the reaction mixture is warmed up and quenched at 0 °C.
(CDCl3, 300 MHz) δ 1.20 and 1.21 (2 × t, J ) 7.0 Hz, 6H), 1.34
(m, 9H), 1.53 (d, JHP ) 12.6 Hz, 3H), 2.41 (ddd, JHP ) 20.8 Hz,
JHP ) 14.4 Hz, J ) 15.2 Hz, 1H), 2.68 (ddd, JHP ) 21.7 Hz,
JHP ) 12.9 Hz, J ) 15.2 Hz, 1H), 3.61-3.78 (m, 5H), 4.08-4.41
(m, 5H). 31P NMR (CDCl3, 121.47 MHz) δ 22.1 and 40.09 (2 × d,
JPP ) 20.0 Hz).
General Procedure for Alkyl Chlorides and Tosylates
(Table 2, Entry 6): Octyl-phenyl-phosphinic Acid Ethyl Ester.18
Neat ethyl phenyl-H-phosphinate (0.510 g, 3 mmol) was placed
under vacuum in a dry two-neck flask 10 min before use. Anhydrous
THF (10 mL) was then added under nitrogen. The flask was placed
at -78 °C and deoxygenated under vacuum for 5 min. The reaction
flask was back-filled with nitrogen, and LHMDS (1.0 M in THF,
3 mL, 3 mmol) was added at -78 °C. After 10 min, n-octyl chloride
(510 µL, 3 mmol) was added under N2. After addition, the reaction
mixture was slowly allowed to warm up to rt. The solution was
then refluxed overnight under N2. After cooling, the reaction mixture
was quenched with NH4Cl/brine, extracted with ethyl acetate (3×),
dried over anhydrous MgSO4, and concentrated in vacuo. The
resulting oil was purified by column chromatography (silica, EtOAc/
hexanes 40:60) to afford the desired product (51%). RN: [119079-
Representative Procedure for Hindered Iodides (Table 2,
Entry 8): Isopropyl-phenyl-phosphinic Acid Ethyl Ester.20 Neat
ethyl phenyl-H-phosphinate (510 mg, 3 mmol) was placed under
vacuum in a dry two-neck flask 10 min before use. Anhydrous
THF (10 mL) was then added under nitrogen. The flask was placed
at -78 °C and deoxygenated under vacuum for 5 min. The reaction
flask was back-filled with nitrogen, and LHMDS (1.0 M in THF,
3 mL, 3 mmol) was added at -78 °C. After 10 min, isopropyl
iodide (300 µL, 3 mmol) was added under N2. After addition, the
temperature of the solution was slowly allowed to warm to rt. The
solution was then refluxed for 6 h. After cooling, the reaction
mixture was quenched with NH4Cl/brine, extracted with ethyl
acetate (3×), dried over anhydrous MgSO4, and concentrated in
vacuo. The resulting oil was purified by column chromatography
(silica, EtOAc/hexanes 80:20) to afford the desired product (45%).
1
17-3]. H NMR (CDCl3, 300 MHz) δ 0.85 (t, J ) 6.7 Hz, 3 H),
1.22-1.35 (m, 10 H), 1.29 (t, J ) 7.0 Hz, 3 H), 1.46-1.60
(m, 2 H), 1.81-2.04 (m, 2 H), 4.84 and 4.08 (m, 2 H), 7.45-7.60
(m, 3 H), 7.76-7.85 (m, 2 H).
1
RN: [53716-14-6]. H NMR (CDCl3, 300 MHz) δ 1.04 (d, J )
General Procedure for Alkyl Bromides (Table 2, Entry 4).
Neat ethyl phenyl-H-phosphinate (0.510 g, 3 mmol) was placed
under vacuum in a dry two-neck flask 10 min before use. Anhydrous
THF (10 mL) was then added under nitrogen. The flask was placed
at -78 °C and deoxygenated under vacuum for 5 min. The reaction
flask was back-filled with nitrogen, and LHMDS (1.0 M in THF,
3 mL, 3 mmol) was added at -78 °C. After 10 min, n-octyl bromide
(520 µL, 3 mmol) was added under N2. After addition, the
temperature of the solution was slowly allowed to warm to rt. After
3 h at rt, the reaction mixture was quenched with NH4Cl/brine,
extracted with ethyl acetate (3×), dried over anhydrous MgSO4,
and concentrated in vacuo. The resulting oil was purified by column
chromatography (silica, EtOAc/hexanes 40:60) to afford octyl-
phenyl-phosphinic acid ethyl ester in 71% yield.
General Procedure for Alkyl Iodides and Triflates (Table 3,
Entry 8): [(1,1-Diethoxy-ethyl)-ethoxy-phosphinoylmethyl]-
phosphonic Acid Diethyl Ester.19 Neat ethyl (l,l-diethoxyethyl)-
phosphinate (630 mg, 3 mmol) was placed under vacuum in a dry
two-neck flask 10 min before use. Anhydrous THF (10 mL) was
then added under nitrogen. The flask was placed at -78 °C and
deoxygenated under vacuum for 5 min. The reaction flask was back-
filled with nitrogen, and LHMDS (1.0 M in THF, 3 mL, 3 mmol)
was added at -78 °C. After 10 min, alkyl triflate (0.945 g,
3.15 mmol) dissolved in THF (6 mL) was added under N2. After
addition, the temperature of the solution was slowly allowed to
warm to rt. After 1 h at rt, the reaction mixture was quenched with
NH4Cl/brine, extracted with ethyl acetate (3×), dried over anhy-
drous MgSO4, and concentrated in vacuo. The resulting oil was
purified by column chromatography (silica, EtOAc/MeOH 95:5)
to afford the desired product (81%). RN: [179015-83-9]. 1H NMR
7.0 Hz, 1.5H), 1.10 (d, J ) 7.0 Hz, 1.5H), 1.16 (d, J ) 7.0 Hz,
1.5H), 1.22 (d, J ) 7.0 Hz, 1.5H), 1.32 (t, J ) 7 Hz, 3H), 2.0-
2.15 (m, 1H), 3.80-3.95 (m, 1H), 4.05-4.20 (m, 1H), 7.45-7.60
(m, 3H), 7.70-7.80 (m, H). 31P NMR (CDCl3, 121.47 MHz) δ
54.60 (s).
Representative Procedure with Pyridinium Salts (Table 3,
Entry 6b): (1,1-Diethoxy-ethyl)-pyridin-3-ylmethyl-phosphinic
Acid Ethyl Ester. Neat ethyl (l,l-diethoxyethyl)phosphinate
(0.630 g, 3 mmol) was placed under vacuum in a dry two-neck
flask 10 min before use. Anhydrous THF (10 mL) was then added
under nitrogen. The flask was placed at -78 °C and deoxygenated
under vacuum for 5 min. The reaction flask was back-filled with
nitrogen, and LHMDS (1.0 M in THF, 3 mL, 3 mmol) was added
at -78 °C. In a second dry two-neck flask, LHMDS (1.0 M in
THF, 3 mL, 3mmol) was added to a solution of 2-(bromomethyl)-
pyridine hydrobromide (0.759 g, 3 mmol) in anhydrous THF
(5 mL), at -78 °C under N2. After 10 min, the first solution was
added to the second one. After 10 min at -78 °C, the temperature
of the solution was slowly allowed to warm to rt. After 3 h at rt,
the reaction mixture was quenched with NH4Cl/brine, extracted with
ethyl acetate (3×), dried over anhydrous MgSO4, and concentrated
in vacuo. The resulting oil was purified by column chromatography
(silica, EtOAc 100%) to afford the desired product (60%). 1H NMR
(CDCl3, 300 MHz) δ 1.12-1.29 (m, 9H), 1.50 (d, JHP ) 11.4 Hz,
3H), 3.11 and 3.23 (ABX system, JAB ) 14.6 Hz, JBX ) 8.2 Hz,
JAX ) 8.6 Hz, 2H), 3.58-3.88 (m, 4H), 4.08 (qt, J ) 7.3 Hz, 2H),
7.25 (dd, J ) 7.9 Hz, J ) 3.5 Hz, 1H), 7.67-7.74 (m, 1H), 8.48-
8.51 (m, 2H). 13C {1H} NMR (CDCl3, 75.45 MHz) δ 15.6 (d, JPOCC
) 20.7 Hz), 16.7 (d, JPCC ) 5.2 Hz), 20.6 (d, JPOCC ) 12.4 Hz),
30.0 (d, JPC ) 78 Hz), 57.9 (d, JPOC ) 7.8 Hz), 58.7 (d, JPOC
)
4.6 Hz), 62.3 (d, JPOC ) 6.9 Hz), 101.5 (d, JPC ) 142 Hz), 123.4,
127.3 (d, JPCC ) 8.3 Hz), 137.8 (d, JPCCCC ) 4.6 Hz), 148.2 (d,
JPCCC ) 3.2 Hz), 151.1 (d, JPCCCC ) 6.0 Hz). 31P NMR (CDCl3,
121.47 MHz) δ 44.21 (s). HRMS ([M + H]+ ion by direct probe):
calcd for C14H25O4P 302.1521, obsd 302.1526.
Representative Procedure with Epoxides (Scheme 1): (2-
Hydroxy-hex-5-enyl)-phenyl-phosphinic Acid Ethyl Ester 2. Neat
ethyl phenyl-H-phosphinate (0.510 mg, 3 mmol) was placed under
vacuum in a dry two-neck flask 10 min before use. Anhydrous
THF (10 mL) was then added under nitrogen. The flask was placed
at -78 °C and deoxygenated under vacuum for 5 min. The reaction
flask was back-filled with nitrogen, and LHMDS (1.0 M in THF,
3 mL, 3 mmol) was added at -78 °C. After 10 min, 1,2-epoxy-
(12) For examples of epoxide-opening using the silicon method, see refs
1c and 1k.
(13) CGP 36742/SGS742: (a) Chebib, M.; Vandenberg, R. J.; Froestl,
W.; Johnston, G. A. R. Eur. J. Pharmacol. 1997, 329, 223. (b) Pittaluga,
A.; Vaccari, D.; Raiteri, M. J. Pharmacol. Exp. Ther. 1997, 283, 82. (c)
Steulet, A.-F.; Moebius, H.-J.; Mickel, S. J.; Stoecklin, K.; Waldmeier, P.
C. Biochem. Pharmacol. 1996, 51, 613.
(14) Depre`le, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745.
(15) Dumond, Y. R.; Baker, R. L.; Montchamp, J.-L. Org. Lett. 2000,
2, 3341.
(16) Ross, F. C.; Botting, N. P.; Leeson, P. D. Bioorg. Med. Chem. Lett.
1996, 6, 2643.
(17) (a) Zeiss, H.-G. J. Org. Chem. 1991, 56, 1783. (b) Maier, L.; Rist,
G. Phosphorus Sulfur 1983, 17, 21. (c) Tan, S.; Evans, R.; Singh, B. Amino
Acids 2006, 30, 195. (d) Evstigneeva, Z. G.; Solov’eva, N. A.; Sidel’nikova,
L. I. Appl. Biochem. Microbiol. 2003, 39, 539.
(18) Pudovik, A. N.; Konovalova, I. V. J. Gen. Chem. USSR 1960, 30,
2328.
(19) Luke, G. P.; Shakespeare, W. C. Synth. Commun. 2002, 32, 2951.
(20) (a) Zymanczyk-Duda, E.; Lejczak, B.; Kafarski, P. Phosphorus,
Sulfur Silicon Relat. Elem. 1996, 112, 47. (b) Siddall, T. H., III; Prohaska,
C. A. J. Am. Chem. Soc. 1962, 84, 2502.
J. Org. Chem, Vol. 72, No. 8, 2007 2855

Abrunhosa-Thomas et al.
5-hexene (340 µL, 3 mmol) was added followed by the addition of
boron trifluoride etherate (380 µL, 3 mmol) under N2. After
addition, the temperature of the solution was slowly allowed to
warm to rt. After 2 h at rt, the reaction mixture was quenched with
NH4Cl/brine, extracted with ethyl acetate (3×), dried over anhy-
drous MgSO4, and concentrated in vacuo. The resulting oil was
purified by column chromatography (silica, EtOAc 100%) to afford
-78 °C. After 15 min, condensed chlorodifluoromethane (around
5.0 g, 58.0 mmol) was added under N2. After addition, the
temperature of the solution was kept at -78 °C for 10 min, then
slowly allowed to warm to 0 °C. After 10 min at 0 °C, the reaction
mixture was quenched with a saturated solution of NH4Cl/brine,
extracted with EtOAc (3×), and then dried over anhydrous MgSO4.
Concentration in vacuo gave an oil that was purified by column
chromatography (silica, EtOAc/hexanes 30:70) to afford the desired
product (71%). RN: [139474-89-8]. 1H NMR (CDCl3, 300 MHz)
δ 1.22 (t, J ) 7.0 Hz, 6H), 1.39 (t, J ) 7.0 Hz, 3H), 1.58 (d, JHP
) 12.0 Hz, 3H), 3.63-3.87 (m, 4H), 4.29-4.39 (m, 2H), 6.08
(dt, JHF ) 27.5 Hz, JHF ) 48.9 Hz, 1H). 31P NMR (CDCl3,
121.47 MHz) δ 27.5 (t, JFP ) 71.4 Hz). 19F NMR (CDCl3,
282.30 MHz) δ -135.31 (ddt, JFH ) 21.8 Hz, JFP ) 71.4 Hz,
JFH ) 49.5 Hz).
1
the desired product (85%). H NMR (CDCl3, 300 MHz) δ 1.31
(t, J ) 7.0 Hz, 3H), 1.53-1.72 (m, 2H), 1.91-2.19 (m, 5H), 3.87
(m, 1H), 4.07-4.23 (m, 2H), 4.88-5.06 (m, 2H), 5.78 (tqd, J )
6.4 Hz, J ) 10.5 Hz, 1H), 7.46-7.83 (m, 5H). 13C {1H} NMR
(CDCl3, 75.45 MHz) δ 16.7 (d, JPOCC ) 6.6 Hz), 29.82, 36.2, 37.2
(d, JPC ) 84.9 Hz), 37.5 (d, JPCCCC ) 3.5 Hz), 37.6 (d, JPCCCC
)
3.2 Hz), 61.1 (d, JPOCC ) 6.9 Hz), 61.2 (d, JPOCC ) 6.6 Hz), 65.6,
66.4 (d, JPOCC ) 6.0 Hz), 128.9 (d, JPCC ) 2.3 Hz), 129.1
(d, JPCC ) 2.0 Hz), 130.4 (d, JPC ) 128 Hz), 131.5 (d, JPCCC
)
10.4 Hz), 131.8 (d, JPCCC ) 10.1 Hz), 132.1, 132.8, 132.9, 138.2
(d, JPCCCC ) 5.5 Hz). 31P NMR (CDCl3, 121.47 MHz) δ 44.26 (s),
55.74 (s). HRMS (M+ by EI+): calcd for C14H21O3P 268.1228,
obsd 268.1228.
Representative Procedure with Freon (Table 3, Entry 9):
Difluoromethyl-(1,1-diethoxy-ethyl)-phosphinic Acid Ethyl Ester.1d
Neat ethyl (l,l-diethoxyethyl)phosphinate (12.0 g, 57.1 mmol) was
placed under vacuum in a dry two-neck flask equipped with a cold
finger 10 min before use. Anhydrous THF (80 mL) was then added
under N2. The flask was cooled to -78 °C and deoxygenated under
vacuum for 5 min. The reaction flask was back-filled with nitrogen,
then LHMDS (1.0 M in THF, 57.1 mL, 57.1 mmol) was added at
Acknowledgment. The National Institute of General Medical
Sciences/NIH (Grant R01 GM067610) is gratefully acknowl-
edged for financial support. J.-L.M. thanks Gerry Katchinska
for a generous gift of CF2HCl and Dr. Lae¨titia Coudray for
helpful discussions.
Supporting Information Available: Representative NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO062436O
2856 J. Org. Chem., Vol. 72, No. 8, 2007