Radical reaction of sodium hypophosphite with terminal alkynes: Synthesis of 1,1-bis-H-phosphinates

Article abstract of DOI:10.1021/ol052533o

(Chemical Equation Presented) The room-temperature radical addition of sodium hypophosphite to terminal alkynes produces the previously unknown 1-alkyl-1,1-bis-H-phosphinates in moderate yield. The reaction is initiated by R₃B and air and proceeds under mild conditions in an open container. The bissodium salts precipitate spontaneously from the reaction mixtures, thus providing a simple purification procedure and the opportunity for multigram synthesis. The 1,1-bis-H-phosphinate products are novel precursors of the biologically important 1,1-bisphosphonates.

Full text of DOI:10.1021/ol052533o

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5909-5912
Radical Reaction of Sodium
Hypophosphite with Terminal Alkynes:
Synthesis of 1,1-Bis-H-phosphinates
Sonia Gouault-Bironneau, Sylvine Depre`le, Amber Sutor, and
Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian UniVersity,
Fort Worth, Texas 76129
j.montchamp@tcu.edu
Received October 19, 2005
ABSTRACT
The room-temperature radical addition of sodium hypophosphite to terminal alkynes produces the previously unknown 1-alkyl-1,1-bis-H-
phosphinates in moderate yield. The reaction is initiated by R3B and air and proceeds under mild conditions in an open container. The
bissodium salts precipitate spontaneously from the reaction mixtures, thus providing a simple purification procedure and the opportunity for
multigram synthesis. The 1,1-bis-H-phosphinate products are novel precursors of the biologically important 1,1-bisphosphonates.
We recently reported a novel and general approach toward
H-phosphinate derivatives based on the room-temperature
radical addition of hypophosphorous compounds to alkenes
(eq 1).1 Since then, we have studied the reactions of alkynes
on the conditions employed (eq 2). A mixture of trans- and
cis-alkenyl-H-phosphinic acids was produced as the major
component, along with minor amounts of disubstituted 1,2-
bis-H-phosphinic acids. Nifant’ev had also investigated
alkenes under the same conditions.4 Previously, we found
that our milder reaction conditions considerably expanded
the scope of H-phosphinates, which could be produced in
terms of both functional group tolerance on the alkene and
the hypophosphorous reagent employed.1 These differences
prompted the study of alkynes as substrates under our R3B/
air and room-temperature conditions.
As a model study, the reaction of sodium hypophosphite
with 1-hexyne was investigated using Et3B/air to promote
radical formation. The results are summarized in Table 1.
Methanol was initially selected as solvent because sodium
with sodium hypophosphite under similar conditions and
discovered the formation of a new class of compounds:
1-alkyl-1,1-bis-H-phosphinates.2 We now report the results
of this study.
The thermal, peroxide-initiated radical reaction of hypo-
phosphorous acid with alkynes has been studied by Nifant’ev
and co-workers.3 Several products were identified depending
(1) Depre`le, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745.
(2) Montchamp, J.-L.; Depre`le, S. U.S. Patent Number US 6,781,011
B2, 2004.
(3) (a) Nifant’ev, E. E.; Solovetskaya, L. A.; Maslennikova, V. I.;
Magdeeva, R. K.; Sergeev, N. M. J. Gen. Chem. USSR 1986, 56, 680. (b)
Nifant’ev, E. E.; Magdeeva, R. K.; Solovetskaya, L. A.; Sergeev, N. M. J.
Gen. Chem. USSR 1984, 54, 630.
(4) (a) Nifant’ev, E. E.; Magdeeva, R. K.; Shchepet’eva, N. P. J. Gen.
Chem. USSR 1980, 50, 1416. (b) 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.
10.1021/ol052533o CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/02/2005

Table 1. Influence of Reaction Conditions with 1-Hexynea
Table 2. Scope of Alkyne Radical Hydrophosphinylation
entry NaH2PO2 equiv
solvent
isolated yieldb
1
2c
3
4
5
6
7
8
9
2.5
2.5c
2.5
6.0
6.0
6.0
6.0
6.0
6.0
MeOH
13
0c
MeOHc
MeOH/acetone (5:1)
MeOH
44
52
23
27
57
67
67
0
MeOH/H2O (5:1)
MeOH/CH3CN (5:1)
MeOH/acetone (5:1)
MeOH/DMF (5:1)
MeOH/dioxane (5:1)
THF/H2O (2:1)
MeOH
10
11
12
6.0
10.0
10.0
62
65
MeOH/dioxane (5:1)
a Reactions were conducted in a flask open to air at room temperature,
using Et3B (1 equiv) in hexane (1 M) in reagent-grade solvent. Unless
otherwise noted, the concentration of 1-hexyne before addition of Et3B was
0.2 M. b All yields are isolated after filtration and washing with cold
methanol. c Concentration was 0.1 M.
hypophosphite has no significant solubility in other common
organic solvents at room temperature. Interestingly, the novel
1,1-bis-H-phosphinate was always obtained as the major
product (the remaining filtrate contains some unreacted
alkyne, along with small amounts of the 1,2-disubstituted
isomer and, in some cases, traces of the alkenyl intermediate).
Additionally, the 1,1-bis-H-phosphinate disodium salt pre-
cipitated spontaneously from the reaction mixture, thereby
allowing easy isolation. The only 1,1-bis-H-phosphinate
derivatives reported in the literature are the unsubstituted
ethyl and isopropyl esters of the parent acid,5 which were
obtained from Cl2PCH2PCl2.6
Under the conditions we used with alkenes,1 only a small
amount of precipitate formed (entry 1). As expected,
decreasing the concentration lowered the yield further (entry
2) because of both a less-efficient chain reaction and an
increased solubility of the product which impedes its
recovery. Addition of a cosolvent significantly increases the
yield (entry 3). Because 2.5 equiv of NaH2PO2 was optimum
for reaction with olefins and because bis addition is required
with alkynes, increased amounts of hypophosphite were tried.
Not surprisingly, this resulted in significant improvements
(compare entry 11 with entry 4 and entry 1). Various
cosolvents were also tried. Water (entry 5) and acetonitrile
(entry 6) were unsatisfactory, whereas acetone (entry 7),
DMF (entry 8), or dioxane (entry 9) afforded good yields of
1,1-bis-H-phosphinate. At this point, further increasing the
amount of sodium hypophosphite had little effect (entry 12
vs 9). Therefore, the conditions in entry 9 appeared nearly
ideal.
a Reactions were conducted in a flask open to air at room temperature,
using reagent-grade solvent(s) with NaH2PO2 (6 equiv) and Et3B (1 equiv,
1 M in hexane). Method A: MeOH. Method B: MeOH/dioxane (5:1).
Method C: after a run conducted, as in Method B, the filtrate is concentrated
and redissolved in the solvent mixture along with NaH2PO2 (6 equiv), and
Et3B is added. The yield corresponds to the combined yield after both runs.
For additional details, see the Supporting Information. b 1,1-Bis-H-phos-
phinates were isolated by simple filtration after washing with cold methanol
in >95% purity. c 2 equiv of Et3B were used.
give the corresponding 1,1-bis-H-phosphinate which always
precipitated out of the reaction mixture. Initially, the addition
was investigated using unoptimized conditions (method A,
Table 2). Reaction in methanol generally afforded lower
yields than when dioxane was employed as a cosolvent
(method B, Table 2, entry a vs b). Polar alkynes also give
better yields possibly because of their higher solubility in
methanol. A variety of functional groups are tolerated.
Although the yields were sometimes low, the reaction is
convenient to run even on a large scale and does not require
particular precautions. Gas chromatographic analysis of the
filtrate after low-yielding reactions shows that the alkyne
starting material remains in significant quantity. Thus, a
“recycling” strategy was developed to increase conversion:
after the first run, the filtrate is concentrated, taken up in
the solvent, and more NaH2PO2 and Et3B are added. For
example, using this method, 4-phenyl-1-butyne (Table 2,
entry 11b) yields the bisphosphinate in 21% yield in the first
run and in 35% yield in the second run, for a 56% overall
yield (method C, Table 2).
Next, the scope of the reaction was studied on a variety
of terminal alkyne substrates (Table 2). All alkynes react to
(5) Novikova, Z. S.; Odinets, I. L.; Lutsenko, I. F. J. Gen. Chem. USSR
1987, 57, 459.
(6) Hietkamp, S.; Sommer, H.; Stelzer, O. Chem. Ber. 1984, 117, 3400.
5910
Org. Lett., Vol. 7, No. 26, 2005

Bisphosphonates are an important class of biologically
active compounds, used, for example, in the treatment of
bone diseases such as osteoporosis7 or to prepare conjugates
with high bone affinity.8 Thus, the oxidative conversion of
1,1-bis-H-phosphinates into the corresponding bisphospho-
nates was investigated. H-Phosphinic acids have been
converted into phosphonates through a variety of methods.9
The acids are more reactive toward oxidation than the
corresponding neutral salts because the P(V)-P(III) tautom-
erism of the phosphinylidene group is catalyzed by non-
neutral conditions. However, we found ozonolysis to be a
practical method to directly convert the 1,1-bis-H-phos-
phinate disodium salt into the corresponding phosphonate
(eq 3). The same bisphosphonate was recently shown by
Szajnman and co-workers to have significant activity on
Trypanosoma cruzi farnesyl pyrophosphate synthase (Ki )
0.47 µM; IC50 ) 5.67 µM).10 Other reagents can also be
employed (H2O2, NaOCl, Br2), but ozonolysis was generally
found to be more convenient.11
Scheme 1. Preparation of a Steroid-Bisphosphonate
Conjugate
teoporosis and to decrease the well-known problems associ-
ated with hormone replacement therapy. Epiandrosterone was
reacted with propargyl chlorofomate to form the correspond-
ing carbonate 1 in nearly quantitative yield. Because of the
solubility profile of the steroid, a ternary solvent mixture
was employed for the radical reaction with NaH2PO2, which
then afforded 1,1-bis-H-phosphinate 2 as a white solid.
Finally, oxidation with ozone produced the bisphosphonate-
steroid conjugate 3. Thus, the present reaction can be used
for the expeditious synthesis of bisphosphonates. Literature
syntheses of steroid-bisphosphonate conjugates require time-
consuming multistep sequences, whereas our synthesis of 3
can be conducted quickly with a reasonable overall yield.13
The present reaction has obvious potential for the prepara-
tion of bisphosphonate libraries from terminal alkyne precur-
sors. Additionally, it avoids the cumbersome and sometimes
problematic8g,12a protection-deprotection strategies associ-
ated with the alkylation of methylenebisphosphonate esters.
Finally, the esterification of a 1,1-bis-H-phosphinate was
studied. It was found that a direct esterification of the sodium
salt with PivCl/i-PrOH delivered the corresponding ester as
a mixture of stereoisomers in good yield (eq 4).
The unique potential of 1,1-bis-H-phosphinates to function
as precursors of bisphosphonates was then realized with the
preparation of a steroid conjugate (Scheme 1). Bisphospho-
nate-steroid conjugates12 have been proposed as a method
to direct hormones to the bone for the treatment of os-
(7) (a) Rodan, G. A. Annu. ReV. Pharmacol. Toxicol. 1998, 38, 375. (b)
Mundy, G. R. Annu. ReV. Med. 2002, 53, 337. (c) Prestwood, K. M.;
Pilbeam, C. C.; Raisz, L. G. Annu. ReV. Med. 1995, 46, 249. (d) Fleisch,
H. Bisphosphonates in Bone Disease; Academic Press: San Diego, 2000.
(e) Bisphosphonate on Bones; Bijvoet, O. L. M., Fleisch, H. A., Canfield,
R. E., Russell, R. G. G., Eds.; Elsevier: Amsterdam, 1995.
(8) Bisphosphonate conjugates for bone targeting: (a) [methotrexate]
Sturtz, G.; Appe´re´, G.; Breistol, K.; Fodstad, O.; Schwartsmann, G.;
Hendriks, H. R. Eur. J. Med. Chem. 1992, 27, 825. (b) [doxorubicin] Fabulet,
O.; Sturtz, G. Phosphorus, Sulfur Silicon 1995, 101, 225. (c) [protein]
Uludag, H.; Gao, T.; Wohl, G. R.; Kantoci, D.; Zernicke, R. F. Biotechnol.
Prog. 2000, 16, 1115. (d) [protein] Uludag, H.; Kousinioris, N.; Gao, T.;
Kantoci, D. Biotechnol. Prog. 2000, 16, 258. (e) [fluoroquinolones]
Herczegh, P.; Buxton, T. B.; McPherson, J. C., III.; Kovacs-Kulyassa, A.;
Brewer, P. D.; Sztaricskai, F.; Stroebel, G. G.; Plowman, K. M.; Farcasiu,
D.; Hartmann, J. F. J. Med. Chem. 2002, 45, 2338. (f) [carboranes]
Kultyshev, R. G.; Liu, J.; Liu, S.; Tjarks, W.; Soloway, A. H.; Shore, S. G.
J. Am. Chem. Soc. 2002, 124, 2614. (g) [prostaglandin E2 conjugate] Gil,
L.; Han, Y.; Opas, E. E.; Rodan, G. A.; Ruel, R. J.; Seedor, J. G.; Tyler, P.
C.; Young, R. N. Bioorg. Med. Chem. 1999, 7, 901.
(9) Oxidation of H-phosphinates: [H2O2] (a) Barton, D. H. R.; Vonder
Embse, R. A. Tetrahedron 1998, 54, 12475. (b) Kehler, J.; Hansen, H. I.;
Sanchez, C. Bioorg. Med. Chem. Lett. 2000, 10, 2547. [Br2] (c) Baylis, E.
K.; Campbell, C. D.; Dingwall, J. G. J. Chem. Soc., Perkin. Trans 1 1984,
2845. (d) Fastrez, J.; Jespers, L.; Lison, D.; Renard, M.; Sonveaux, E.
Tetrahedron Lett. 1989, 30, 6861. (e) Hamilton, R.; Walker, B.; Walker,
B. J. Tetrahedron Lett. 1995, 36, 4451. (f) Drag, M.; Grembecka, J.;
Kafarski, P. Phosphorus, Sulfur Silicon 2002, 177, 1591. [NaIO4] (g)
Vitharana, D.; France, J. E.; Scarpetti, D.; Bonneville, G. W.; Majer, P.;
Tsukamoto, T. Tetrahedron: Asymmetry 2002, 13, 1609. [I2] (h) Albouy,
D.; Brun, A.; Munoz, A.; Etemad-Moghadam, G. J. Org. Chem. 1998, 63,
7223.
(10) Szajnman, S. H.; Montalvetti, A.; Wang, Y.; Docampo, R.;
Rodriguez, J. B. Bioorg. Med. Chem. Lett. 2003, 13, 3231.
(11) Depending on the substrate and oxidizer, variable amounts of
phosphate can also form through P-C bond cleavage. Details will be
provided in the full paper.
In conclusion, we have developed a simple and practical
approach to a new class of organophosphorus compounds.
(12) (a) Page, P. C. B.; McKenzie, M. J.; Gallagher, J. A. J. Org. Chem.
2001, 66, 3704. (b) Page, P. C. B.; Moore, J. P. G.; Mansfield, I.; McKenzie,
M. J.; Bowlerb, W. B.; Gallagher, J. A. Tetrahedron 2001, 57, 1837.
(13) A compound related to 3 with an ester tether in place of our
carbonate tether was prepared from Cl2P(O)CH2P(O)Cl2 in five steps and
61% overall yield. However, one of the steps requires a 5 day reaction
time. Circumventing this step results in a five-step sequence with a 26%
overall yield. See ref 12a.
Org. Lett., Vol. 7, No. 26, 2005
5911

Through oxidation, these 1,1-bis-H-phosphinates can be
converted into 1,1-bisphosphonates which are biologically
important compounds. An intriguing possibility which
remains for further studies would be if in vivo oxidation of
the 1,1-bis-H-phosphinates can take place14 because these
compounds would then act as novel bisphosphonate pro-
drugs.15 Further investigations to study the reactivity of the
1,1-bis-H-phosphinates and to prepare various conjugates are
currently underway and will be reported in a full account.
Acknowledgment. We thank the National Institute of
General Medical Sciences/NIH (R01 GM067610) for the
support of this research.
Supporting Information Available: Representative ex-
perimental procedures and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL052533O
(15) The highly-charged nature of bisphosphonates decreases uptake and
causes the rapid excretion of these compounds. For examples of bisphos-
phonate prodrugs, see: (a) Ezra, A.; Hoffman, A.; Breuer, E.; Alferiev, I.
S.; Mo¨nkko¨nen, J.; Hanany-Rozen, N. E.; Weiss, G.; Stepensky, D.; Gati,
I.; Cohen, H.; To¨rma¨lehto, S.; Amidon, G. L.; Golomb, G. J. Med. Chem.
2000, 43, 3641. (b) Niemi, R.; Vepsa¨la¨inen, J.; Taipale, H.; Ja¨rvinen, T. J.
Med. Chem. 1999, 42, 5053. (c) Ahlmark, M.; Vepsa¨la¨inen, J.; Taipale,
H.; Niemi, R.; Ja¨rvinen, T. J. Med. Chem. 1999, 42, 1473.
(14) There is some evidence for the oxidation of H-phosphinates into
phosphonates in vivo: 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. P(III) compounds such as Et3P have also been
shown to undergo oxidation in vivo: Shaw, C. F., III. Chem. ReV. 1999,
99, 2589.
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