Triethylborane-initiated room temperature radical addition of hypophosphites to olefins: Synthesis of monosubstituted phosphinic acids and esters

Article abstract of DOI:10.1021/jo015876i

A novel and practical approach to monosubstituted phosphinic acid (alkylphosphonous acid) derivatives from hypophosphite salts or esters is described. Phosphorus-centered radical formation is initiated with Et₃B/O₂, and the reaction is conveniently conducted at room temperature in an open flask. In contrast to previously reported conditions for the radical reaction of hypophosphorous acid and sodium hypophosphite (peroxide initiators, acid catalysis, heat), the method proceeds under neutral conditions and therefore tolerates a wide range of functional groups. Previously inaccessible phosphinic acids can be prepared in a single step from cheap starting materials. Excellent selectivity is observed for monoaddition, and symmetrical dialkyl phosphinates do not form in significant amounts. Monosubstituted phosphinic acids are usually obtained in better than 90% purity by a simple extractive workup; however, isolated yields are diminished if the substituent is polar. Because radicals derived from hypophosphites are electrophilic, the reaction is limited to the use of electron-rich olefins. The reaction conditions can also be employed in the room temperature radical reduction of alkyl halides and provide an exceptionally mild and environmentally friendly alternative to the use of tributyltin hydride. The remarkable mild nature of the reaction conditions allows for the radical reaction of sensitive alkyl hypophosphites to occur, in which case, a catalytic amount of Et₃B suffices to deliver alkyl phosphinate esters in reasonable yield.

Full text of DOI:10.1021/jo015876i

J . Org. Chem. 2001, 66, 6745-6755
6745
Tr ieth ylbor a n e-In itia ted Room Tem p er a tu r e Ra d ica l Ad d ition of
Hyp op h osp h ites to Olefin s: Syn th esis of Mon osu bstitu ted
P h osp h in ic Acid s a n d Ester s
Sylvine Depr e` le and J ean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, Texas 76129
j.montchamp@tcu.edu.
Received J une 28, 2001
A novel and practical approach to monosubstituted phosphinic acid (alkylphosphonous acid)
derivatives from hypophosphite salts or esters is described. Phosphorus-centered radical formation
is initiated with Et B/O , and the reaction is conveniently conducted at room temperature in an
3 2
open flask. In contrast to previously reported conditions for the radical reaction of hypophosphorous
acid and sodium hypophosphite (peroxide initiators, acid catalysis, heat), the method proceeds under
neutral conditions and therefore tolerates a wide range of functional groups. Previously inaccessible
phosphinic acids can be prepared in a single step from cheap starting materials. Excellent selectivity
is observed for monoaddition, and symmetrical dialkyl phosphinates do not form in significant
amounts. Monosubstituted phosphinic acids are usually obtained in better than 90% purity by a
simple extractive workup; however, isolated yields are diminished if the substituent is polar. Because
radicals derived from hypophosphites are electrophilic, the reaction is limited to the use of electron-
rich olefins. The reaction conditions can also be employed in the room temperature radical reduction
of alkyl halides and provide an exceptionally mild and environmentally friendly alternative to the
use of tributyltin hydride. The remarkable mild nature of the reaction conditions allows for the
radical reaction of sensitive alkyl hypophosphites to occur, in which case, a catalytic amount of
3
Et B suffices to deliver alkyl phosphinate esters in reasonable yield.
In tr od u ction
limited by the lack of functionalized precursors available.2
Also, the reaction of bis(trimethylsiloxy)phosphine (BTSP)
with alkyl halides, although somewhat general, normally
In connection with our continuing efforts to develop
novel approaches toward the preparation of functional-
ized monosubstituted phosphinic acids (alkylphospho-
nous acids) and their derivatives, we have been investi-
gating the reactivity of hypophosphite salts with unsatu-
rated compounds under radical conditions. We now report
the convenient, mild, and selective reaction of sodium
hypophosphite and related species with alkenes, initiated
at ambient temperature, by trialkylboranes and air.
Monosubstituted phosphinic acids and esters are im-
portant intermediates in the syntheses of biologically
3
requires a large excess of reagent to limit the formation
of disubstituted phosphinic acids and is limited to iodides
and reactive halides.4 In addition, workup is rarely
straightforward due to the phosphine stench usually
associated with the reaction mixture.3 Ultimately, the
development of alternate approaches based on phosphi-
nate synthons with a masked P-H bond has solved a
number of difficulties and provided a general entry into
c,5
6
monosubstituted phosphinic acids. However, cleavage of
the protecting group to unmask the P-H bond requires
1
active compounds and can be prepared by a variety of
methods. However, hydrolysis of dichlorophosphines is
2
(2) Reviews: (a) Frank, A. W. Chem. Rev. 1960, 60, 389. (b)
Nifant’ev, E. E. Russ. Chem. Rev. 1978, 47, 835. (c) The Chemistry of
Organophosphorus Compounds; Hartley, F. R., Ed.; Wiley: New York,
1996; Vol. 4. (d) Quin, L. D. A Guide to Organophosphorus Chemistry;
Wiley: New York, 2000.
(3) (a) Boyd, E. A.; Regan, A. C.; J ames, K. Tetrahedron Lett. 1994,
35, 4223. (b) Boyd, E. A.; Corless, M.; J ames, K.; Regan, A. C.
Tetrahedron Lett. 1990, 31, 2933. (c) Issleib, K.; M o¨ gelin, W.; Balszu-
weit, A. Z. Anorg. Allg. Chem. 1985, 530, 16.
*
To whom correspondence should be addressed.
(1) Representative examples: (a) Tokutake, N.; Hiratake, J .; Katoh,
M.; Irie, T.; Kato, H.; Oda, J . Bioorg. Med. Chem. 1998, 6, 1935. (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) Martin, M.
T.; Angeles, T. S.; Sugasawara, R.; Aman, N. I.; Napper, A. D.; Darsley,
M. J .; Sanchez, R. I.; Booth, P.; Titmas, R. C. J . Am. Chem. Soc. 1994,
1
16, 6508. (d) Baillie, A. C.; Cornell, C. L.; Wright, B. J .; Wright, K.
(4) For example, see: (a) Chen, S.; Coward, J . K. J . Org. Chem. 1998,
63, 502. (b) Nan, F.; Bzdega, T.; Pshenichkin, S.; Wroblewski, J . T.;
Wroblewska, B.; Neale, J .; Kozikowski, A. P. J . Med. Chem. 2000, 43,
772. An, H.; Wang, T.; Maier, M. A.; Manoharan, M.; Ross, B. S.; Cook,
P. D. J . Org. Chem. 2001, 66, 2789. (c) Bujard, M.; Gouverneur, V.;
Mioskowski, C. J . Org. Chem. 1999, 64, 2119. (d) J ones, P. B.; Parrish,
N. M.; Houston, T. A.; Stapon, A.; Bansal, N. P.; Dick, J . D.; Townsend,
C. A. J . Med. Chem. 2000, 43, 3304. (e) Grobelny, D. Synth. Commun.
1989, 19, 1177. (f) Montchamp, J .-L.; Tian, F.; Frost, J . W. J . Org.
Chem. 1995, 60, 6076.
Tetrahedron Lett. 1992, 33, 5133. (e) Karanewsky, D. S.; Badia, M. C.
Tetrahedron Lett. 1986, 27, 1751. (f) Sampson, N. A.; Bartlett, P. A. J .
Org. Chem. 1988, 53, 4500. (g) Karanewsky, D. S.; Badia, M. C.;
Cushman, D. W.; DeForrest, J . M.; Dejneka, T.; Loots, M. J .; Perri, M.
G.; Petrillo, E. W., J r.; Powell, J . R. J . Med. Chem. 1988, 31, 204. (h)
Qiao, L.; Nan, F.; Kunkel, M.; Gallegos, A.; Powis, G.; Kozikowski, A.
P. J . Med. Chem. 1998, 41, 3303. (i) 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.; J aekel, J .;
Karlsson, G.; Klebs, K.; Maitre, L.; Marescaux, C.; Pozza, M. F.;
Schmutz, M.; Steinmann, M. W.; van Riezen, H.; Vassout, A.; Monda-
dori, C.; Olpe, H.-R.; Waldmeier, P. C.; Bittiger, H. J . Med. Chem. 1995,
2
(5) (TMSO) PH (BTSP) is a hazardous, pyrophoric compound.
Decomposition to a polymeric yellow solid of high phosphorus content
is commonly observed in Arbuzov reactions with this compound, and
3
8, 3313. (j) Willems, H. A. M.; Veeneman, G. H.; Westerduin, P.
3
disproportionation leads to formation of PH . See for example: Voronk-
ov, M. G.; Marmur, L. Z.; Dolgov, O. N.; Pestunovich, V. A.; Pokrovskii,
E. I.; Popel, Y. I. J . Gen. Chem. USSR 1971, 41, 2005.
Tetrahedron Lett. 1992, 33, 2075. (k) Tian, F.; Montchamp, J .-L.; Frost,
J . W. J . Org. Chem. 1996, 61, 7313.
1
0.1021/jo015876i CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/05/2001

6
746 J . Org. Chem., Vol. 66, No. 20, 2001
Depr e` le and Montchamp
Sch em e 1. Ra d ica l Rea ction betw een Hyp op h osp h ite Der iva tives a n d Alk en es
acidic or basic conditions which are often not compatible
with highly functionalized molecules. Nevertheless, this
three-step sequence (synthon preparation, functionaliza-
tion, deprotection) is currently the most general ap-
proach, partly because the functionalization step can be
conducted under a wide range of conditions.
some of its salts have emerged as inexpensive and
environmentally benign hydrogen atom donors for the
replacement of tributyltin hydride in radical reductions
and radical cyclizations.11 However, the latter reactions
do not result in the formation of phosphorus-containing
products.
Alternatively, conceiving a direct approach from inex-
pensive precursors such as hypophosphorous acid or its
salts would be ideal, and provided that the reaction is
controlled to stop at the monophosphinic acid stage, it is
the most direct approach conceivable. Furthermore, if the
hazard associated with the use of anhydrous hypophos-
phorous acid is avoided, such an approach would also be
most practical. For these reasons, we have been inter-
ested in developing the chemistry of hypophosphite salts
for the preparation of organophosphorus compounds and
recently reported a general preparation of aryl phosphinic
During studies aimed at the preparation of building
blocks for the synthesis of nonhydrolyzable DNA ana-
logues, we required a method to prepare functionalized
monosubstituted acids or esters. While the addition of
hypophosphorous acid to properly functionalized olefins
appeared most expeditious, it soon became obvious that
the Nifant’ev conditions were not compatible with many
functional groups, due to the strongly acidic nature of
the reaction medium. A neutral source of the phosphorus
radical, such as sodium hypophosphite, might solve this
problem. In fact, Nifant’ev had also investigated the
radical reaction of sodium hypophosphite and found that
7
acids via palladium-catalyzed cross-coupling. To extend
the range of monosubstituted phosphinic acids available,
we have investigated the radical reaction of sodium,
anilinium, and alkyl hypophosphites with olefins.
Preparative radical additions of phosphorus-centered
radicals as P-C bond-forming reactions have been known
10b
good yields of adducts could be obtained (Scheme 1c).
Unfortunately, the reaction requires very high temper-
atures (130-150 °C), a pressurized apparatus (autoclave),
since sodium hypophosphite is soluble only in water or
low-boiling alcohols (methanol, ethanol), and multiple
additions of a peroxide initiator, thereby significantly
complicating the reaction in practice. In an attempt to
diminish these experimental difficulties, Nifant’ev found
it better to generate hypophosphorous acid in situ, by
treating sodium hypophosphite with sulfuric acid. The
acidic nature of the medium thus catalyzes the break-
down of the peroxide initiators, allowing for lower reac-
tion temperatures and more efficient radical formation.
A modification of these conditions was recently intro-
duced by Karenewsky who found that even AIBN could
8
for several decades. Hypophosphorous acid is known to
react with alkenes under the influence of radical initia-
tors (Scheme 1). Williams and Hamilton studied the
3 2
reaction of aqueous H PO
, as early as 1955 (Scheme 1a).9
However, Nifant’ev and co-workers were chiefly respon-
sible for the synthetic development of this reaction, which
has become one of the most convenient methods for the
preparation of phosphinic acids (Reactions b and c of
Scheme 1).10 More recently, hypophosphorous acid and
(
6) (a) Dingwall, J . G.; Ehrenfreund, J .; Hall, R. G.; J ack, J .
1g
be employed in refluxing ethanol. While providing a
Phosphorus Sulfur 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.
major practical breakthrough, these conditions remained
incompatible with acid-sensitive functionalities.
Confronted with this situation, we decided to study
alternate conditions to initiate the radical reaction of
hypophosphite salts and found organoboranes to be
effective and practical for this purpose. Trialkylboranes,
(
f) Bennett, S. N. L.; Hall, R. G. J . Chem. Soc., Perkin Trans. 1 1995,
1
5
1
145.
(7) Montchamp, J .-L.; Dumond, Y. R. J . Am. Chem. Soc. 2001, 123,
966, 3, 1. (b) Halmann, H. Top. Phosphorus Chem. 1967, 4, 49. (c)
3
and especially Et B, have been extensively employed as
Bentrude, W. G. Free Radicals; Kochi, J . K., Ed.; Wiley: New York,
973; Vol. 2, Chapter 22. (d) Bentrude, W. G. The Chemistry of
Organophosphorus Compounds; Hartley, F. R., Ed.; Wiley: New York,
1
(11) (a) Barton, D. H. R.; J ang, D. O.; J aszberenyi, J . C. Tetrahedron
Lett. 1992, 33, 5709. (b) Barton, D. H. R.; J ang, D. O.; J aszberenyi, J .
C. J . Org. Chem. 1993, 58, 6838. (c) McCague, R.; Pritchard, R. G.;
Stoodley, R. J .; Williamson, D. S. Chem. Commun. 1998, 2691. (d)
Graham, S. R.; Murphy, J . A.; Kennedy, A. R. J . Chem. Soc., Perkin
Trans. 1 1999, 3071. (e) Graham, S. R.; Murphy, J . A.; Coates, D.
Tetrahedron Lett. 1999, 40, 2415. (f) Reding, M. T.; Fukuyama, T. Org.
Lett. 1999, 1, 973. (g) Marotta, E.; Righi, P.; Rosini, G. Org. Lett. 2000,
2, 4145. (h) Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar, G.;
Matsugi, M. Org. Lett. 2001, 3, 1157.
1
1
990; Vol. 1, Chapter 14. (e) Stacey, F. W.; Harris, J . F. Org. React.
963, 13, 150.
(
9) Williams, R. H.; Hamilton, L. A. J . Am. Chem. Soc. 1955, 77,
411.
10) (a) Nifant’ev, E. E.; Magdeeva, R. K.; Shchepet’eva, N. P. J .
3
(
Gen. Chem. USSR 1980, 50, 1416. (b) Nifant’ev, E. E.; Koroteev, M.
P. J . Gen. Chem. USSR 1967, 37, 1366. (c) Nifant’ev, E. E.; So-
lovetskaya, L. A.; Maslennikova, V. I.; Magdeeva, R. K.; Sergeev, N.
M. J . Gen. Chem. USSR 1986, 56, 680.

Synthesis of Phosphinic Acids and Esters
J . Org. Chem., Vol. 66, No. 20, 2001 6747
low-temperature initiators, for example, in asymmetric
radical additions.12 Yet, to our knowledge, they were
never employed to generate phosphorus-centered radicals
for P-C bond formation, although one report does
describe the use of sodium hypophosphite and 2 equiv of
tunately, the reactions were sluggish and irreproducible.
These reactions were followed by P NMR, to measure
31
the formation of the phosphinate product and the dis-
appearance of sodium hypophosphite (yields determined
by integrating all the resonances), as well as by capillary
gas chromatography, to monitor the disappearance of
1-octene using an internal standard. Good agreement was
found between 1-octene consumption and sodium octyl-
phosphinate formation.
3 3
Et B as the initiator, as a Bu
SnH replacement.13 We now
report a novel synthesis of monosubstituted phosphinic
acids and esters at ambient temperature and under
neutral conditions, which allows the preparation of
previously inaccessible building blocks. The scope and
limitations of the process are discussed, and the use of
hypophosphite salts is compared with the use of alkyl
hypophosphites.
3
Radical reactions initiated by Et B are often conducted
with a stoichiometric amount and even a 2- to 5-fold
12
excess of the borane. Indeed, better results were
3
obtained with an equimolar amount of Et B relative to
the alkene, but the introduction of air still appeared to
be a delicate parameter. Fortunately, we soon discovered
that when the reaction mixture was treated with Et B
3
Resu lts a n d Discu ssion
Hyp op h osp h ite Sa lts. At the outset, we selected
hypophosphite salts as radical precursors, because they
are readily available, safely handled, and either es-
sentially neutral or much less acidic than hypophospho-
in an open vessel and at room temperature, a rapid (<2
h) and essentially quantitative reaction took place. In one
key experiment leading to this discovery, a methanol
solution of NaH
was treated with Et
under N
2
PO
2
(2.5 equiv) and 1-decene (1 equiv)
B (1 equiv) at room temperature,
rous acid (pK ) 1.23). Some years ago, Barton introduced
a
3
N-ethylpiperidinium hypophosphite (EPHP) as a superior
2
. After 18 h, sodium decylphosphinate was
alternative to the use of tributyltin hydride for radical
obtained in only 18% yield, but exposure of the reaction
mixture to air, at that point, rapidly resulted in a 95%
yield of product.
reductions.1
1a,11b
While this work provided an encouraging
example of the reactivity of hypophosphites in radical
reactions, based on our experience, we preferred anilin-
As expected, stepwise addition of substoichiometric
quantities of Et B also worked well, but this protocol was
3
not retained (nor further optimized) because it was found
less practical. Due to its convenience, the procedure
ium hypophosphite (PhNH
3
‚H
2 3
PO , AHP), which is a
more easily handled and relatively nonhygroscopic crys-
talline salt.7 In addition, sodium hypophosphite (NaH
,14
-
2
PO
2
) was also chosen since it is neutral, widely available,
where Et
vessel was subsequently adopted, and the role of concen-
tration and NaH PO stoichiometry (relative to the
3
B is added to a solution of reactants in an open
and inexpensive. An immediate problem with NaH
2
PO
2
is its insolubility in most organic solvents. A recent report
from the Abbott Laboratories addressed this problem, by
describing the use of a phase-transfer agent in alcoholic
solvents for the large scale deoxygenation of an erythro-
mycin derivative, and demonstrated the usefulness of
2
2
alkene) on the yield and selectivity (monoalkylphosphi-
nate vs dialkylphosphinate) was investigated (Table 1).
31
Again, these runs were conveniently monitored by
P
NMR. Reaction times were fixed at 2 h, as the reactions
were usually fast and no change was observed beyond
that point. As Nifant’ev had also noticed under his
thermal conditions,1 telomer formation was insignifi-
cant. It was not possible to explore subambient temper-
atures because hypophosphite salts rapidly become in-
2 2
NaH PO
in radical reductions.15 However, investigations
aimed at the preparation of organophosphorus com-
pounds from hypophosphites under radical conditions
have apparently not been conducted since Nifant’ev’s
studies.
In preliminary experiments, a methanolic solution of
sodium hypophosphite and 1-octene (or 1-decene) was
treated with 0.1 equiv of triethylborane (as a 1 M solution
in hexane or THF) at room temperature under nitrogen,
and air was introduced in a controlled manner. Unfor-
0a
2 2
soluble upon cooling. Similarly, concentrations of NaH PO
above 0.5 M were not studied because the reaction
mixtures become saturated.
Some disubstitution occurred at high olefin/hypophos-
phite ratios (entries 13 and 14 of Table 1), but mono-
phosphinates were always the major products. AHP has
a slightly greater propensity for disubstitution than
(12) The autooxidation of organoboranes is widely used to generate
alkyl radicals, even at low temperature, see for example: (a) Davies,
A. G.; Ingold, K. U.; Roberts, B. P.; Tudor, R. J . Chem. Soc. B 1971,
2 2
NaH PO (entries 1 vs 9 and 2 vs 10 of Table 1). The
6
98. (b) Brown, H. C.; Midland, M. M. Tetrahedron 1987, 43, 4059. (c)
Barton, D. H. R.; J ang, D. O.; J aszberenyi, J . C. Tetrahedron Lett. 1990,
1, 4681. (d) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc.
J pn. 1991, 64, 403. (e) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron
conversion was lowered when either the reaction was
conducted with lower alkene concentration (entry 1 vs 4
and 5 and entry 9 vs 11 of Table 1) or the hypophosphite
was employed as a limiting reagent (entries 7, 8, and 14).
This can be explained by inefficient chain propagation
and is consistent with previous work on P-centered
3
1
2
1
989, 45, 923. (f) Miyabe, H.; Ueda, M.; Naito, T. Chem. Commun.
000, 2059. (g) Perchyonok, V. T.; Schiesser, C. H. Tetrahedron Lett.
998, 39, 5437. Asymmetric examples: (h) Miyabe, H.; Fujii, K.; Naito,
T. Org. Lett. 1999, 1, 569. (i) Porter, N. A.; Wu, J . H.; Zhang, G.; Reed,
A. D. J . Org. Chem. 1997, 62, 6702. (j) Guindon, Y.; Gu e´ rin, B.; Chabot,
C.; Ogilvie, W. J . Am. Chem. Soc. 1996, 118, 12528. (k) Mase, N.;
Watanabe, Y.; Ueno, Y.; Toru, T. J . Org. Chem. 1997, 62, 7794. (l) Mase,
N.; Watanabe, Y.; Toru, T. Tetrahedron Lett. 1999, 40, 2797. (m)
Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998, 780.
8,10a,b
radicals.
Besides NaH
2 2
PO and AHP, other hypophosphite salts
(triethylammonium, ammonium, and N-ethylpiperidin-
ium) could also be employed with equally satisfactory
results (entries 15-17). Interestingly, even concentrated
3 2
H PO adds itself to 1-octene, although in this case some
(
13) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Chem. Lett. 2000,
04. In one instance, P-C bond formation was observed as a side
reaction (15% yield).
1
(
14) Anilinium hypophosphite (mp 113-114 °C) can be stored at
methyl octylphosphinate is also formed (entry 18).
Reducing the amount of Et B also reduces the amount
of product formed (entry 1 vs 3), although the use of 0.5
equiv of Et B is almost as effective as a stoichiometric
room temperature for months and is handled in air. Commercially
available EPHP (Aldrich) is a low-melting solid (mp 40-43 °C) and is
highly hygroscopic (see ref 11b).
3
(
15) Graham, A. E.; Thomas, A. V.; Yang, R. J . Org. Chem. 2000,
6
5, 2583.
3

6
748 J . Org. Chem., Vol. 66, No. 20, 2001
Depr e` le and Montchamp
Ta ble 1. In flu en ce of th e Rea ction P a r a m eter s on Yield a
Ta ble 2. Ra d ica l Rea ction of Sod iu m Hyp op h osp h ite
w ith Alk en esa
3
1
MH2PO2
equiv
Et3B
equiv
P NMR
% yielde
entry hypophosphiteb
c
concd
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
NaH2PO2
NaH2PO2
NaH2PO2
NaH2PO2
NaH2PO2
NaH2PO2
NaH2PO2
NaH2PO2
PhNH3‚H2PO2
PhNH3‚H2PO2
PhNH3‚H2PO2
PhNH3‚H2PO2
PhNH3‚H2PO2
PhNH3‚H2PO2
Et3NH‚H2PO2
NH4‚H2PO2
EPHP
2.5
2.5
2.5
2.5
2.5
1.5
1.0
0.2
2.5
2.5
2.5
2.0
1.5
0.5
2.5
2.5
3.0
2.5
1.0
0.5
0.1
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.2
0.2
0.2
0.12
0.05
0.2
0.2
0.5
0.2
0.2
0.12
0.09
0.09
0.2
0.2
0.2
0.2
0.2
95
83
25
70
47
66
40
52
92 (5)
90 (6)
75
0
1
2
3
4
5
6
7
8
73
67 (5)
30 (12)
99
90
83
H3PO2
71f
a
All reactions were conducted in reagent grade MeOH for 1.5-2
h, at room temperature in an open flask. Concentration and
number of equivalents are relative to the alkene. NaH2PO2‚H2O
was used. EPHP: 1-ethylpiperidine hypophosphite. H3PO2 was
obtained by concentrating a 50% by wt solution in vacuo. Et3B
1.0 M in hexane or THF was employed). Alkene concentration
after addition of the borane solution. Determined by integration
of all the signals. The number in parentheses indicates the amount
of disubstituted phosphinate formed. When no number is indi-
cated, disubstituted phosphinate was not observed (<2%). The
balance of material is unreacted hypophosphite. f Several other
components are present, including methyl octylphosphinate (20%).
b
c
d
(
e
amount (entries 2 and 10). The same results were
observed with sec-Bu
3
B in place of Et
3
B (data not shown).
a All reactions were conducted in reagent grade MeOH (0.2 M
It should be noted that running the reaction at ambient
temperature results in a much greater intrinsic selectiv-
ity for monosubstitution, whereas Nifant’ev showed that
with a 1:2 hypophosphite/olefin ratio disubstituted phos-
phinates can be formed in very high yield.1 Also, our
results clearly indicate that the formation of a radical is
significantly more difficult from RP(O)(OM)H than from
in alkene) for 1.5-2 h, at room temperature in an open flask.
NaH2PO2/Et3B/alkene ) 2.5:1:1. b Yield of phosphinate salt (M )
c
Na), as determined by integration of all the signals. Isolated by
extraction with aqueous KHSO4/EtOAc (see Experimental Sec-
tion). Monosubstituted phosphinic acid products (M ) H) were
0a
>90% pure. d 1:1 ratio of diastereoisomers. e Isobutylene was
bubbled through the reaction mixture. Yield based on NaH2PO2.
product is also observed in this reaction mixture, but this
component is not extracted upon workup. As expected,
no intramolecular cyclization of the intermediate radical
was observed, in agreement with the Beckwith/Baldwin
rules.16
MH
2
PO
2
. Indeed, when monosubstituted phosphinate
B, a
esters or salts and an olefin were treated with Et
3
low yield of addition was observed, with the exception of
butyl phenylphosphinate (74% yield with 1-decene).
However, these substrates can be reacted under standard
thermal or photochemical initiation, since the solvent,
Some limitations were observed when the reaction was
attempted with electron-deficient olefins. Ethyl acrylate
and styrene were unreactive (5-20% yields, entries 5 and
8
pH, or selectivity is not an issue. From the data shown
in Table 1, a molar ratio of 2.5:1:1 of NaH
2 2
PO /alkene/
6
), and removal of the stabilizers present in the com-
Et B and an alkene concentration of 0.1-0.2 M in
3
mercial reagents did not change this situation. Although
this has not been discussed in any great detail in the
literature, it appears that hypophosphite radicals are
electrophilic and are electronically mismatched with
electron-poor alkenes. Fortunately, the corresponding
methanol were subsequently adopted as the standard
conditions for the formation of the corresponding sodium
monoalkylphosphinate. It is noteworthy that no special
precaution is required as the reaction is not moisture
sensitive (in fact, reagent grade methanol and sodium
hypophosphite hydrate were employed).
4
b,17
phosphinates are accessible from reaction with BTSP
or via the Michael addition of alkyl hypophosphites
With this preliminary data in hand, we then explored
the scope of the reaction with respect to olefinic sub-
strates (Table 2). A variety of alkenes reacted unevent-
fully to deliver good to excellent yields of monosubstituted
phosphinates. Terminal-, 1,2-disubstituted-, and trisub-
stituted-alkenes (entries 1-4, 11-12, and 8-10 of Table
1
7
2
ROP(O)H . While this was not thoroughly investigated
in the present study, an additional factor responsible for
the failed reactions with some olefins may be the in-
creased stability of the intermediate radical, resulting in
inefficient hydrogen abstraction from the hypophosphite
2
1
) undergo the reaction with the expected regioselectivity.
,5-Hexadiene (entry 4) gives the monophosphinic acid
(
16) (a) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073. (b) Beckwith,
A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41, 3925. (c) Baldwin, J .
E. J . Chem. Soc., Chem. Commun. 1976, 734.
as the major product. A small amount of bis addition

Synthesis of Phosphinic Acids and Esters
J . Org. Chem., Vol. 66, No. 20, 2001 6749
Sch em e 2. P ostu la ted Mech a n ism in th e Rea ction of Na H
2
P O
2
w ith Allyltr ibu tyltin , w ith a n d w ith ou t
Ra d ica l Recyclin g
1
salt, and thus the failure to maintain chain propagation
through the regeneration of the P-centered radical. Some
olefinic substrates supporting this hypothesis are iso-
prene (entry 7) and allyltributyltin, both of which did not
produce useful amounts of phosphinate products (0% and
identification of the products was conducted by H NMR
analysis of the crude reaction mixture and comparison
with the spectrum of an authentic sample4 of allylphos-
phinic acid.
a
Besides the practical convenience of ambient temper-
ature, an open vessel, and short reaction time, the
usefulness of our reaction is better demonstrated with
more elaborate substrates (Table 3), especially alkenes
displaying acid-sensitive functionalities not compatible
with the Nifant’ev conditions (entries 1-3, 5, and 9 of
Table 3). In an ongoing synthetic project, we required
2-hydroxyethylphosphinic acid, which is a type of synthon
that is not readily available. Using our reaction, protected
2-hydroxyethylphosphinic acid can be obtained in good
2
7%, respectively). Interestingly, when allyltributyltin
was reacted in the presence of cyclohexyl bromide as an
alkyl radical recycling stratagem, the yield of adduct
increased to 77% (27-28 ppm). Although this reaction
is of little synthetic use, it illustrates how the radical
chain propagation can be sustained through the use of
such a recycling strategy. The postulated mechanism is
shown in Scheme 2. The tin radical does not efficiently
abstract the hypophosphite hydrogen, but it rapidly
reduces cyclohexyl bromide to produce an alkyl radical
capable of carrying the chain by generating the required
P-centered radical (similar to Roberts’ polarity reversal
yield and in a single step from NaH
Vinyl pivalate and vinyl acetate were reacted with
NaH PO under the standard conditions (entries 1 and
2 2
PO and enol esters.
2
2
1
8
catalysis ). Depending on the conditions, addition to
sodium allylphosphinate can be observed to form the
corresponding bisphosphinate. The latter radical reaction
is representative of the addition to other alkenes, which
does not require a separate radical-recycling step (see
2 of Table 3) to provide the corresponding esters in 60-
80% yields, which could be isolated in good purity after
a simple extractive workup. If the phosphinate ester is
desired, the acid can be esterified as previously re-
ported.19 Other acid-sensitive (or base-sensitive) sub-
strates were tolerated without further complication
(Table 3). If desired, the protecting group can be cleaved
during workup, although this was generally avoided in
order to facilitate further manipulations. Another inter-
esting application is the formation of (3-aminopropyl)-
phosphinic acid (CGP27492), which is a GABA mimic and
“normal alkene addition” pathway in Scheme 2). In this
experiment, after acidification of the aqueous layer,
(
17) BTSP reaction: (a) J ackson, P. F.; Cole, D. C.; Slusher, B. S.;
Stetz, S. L.; Ross, L. E.; Donzanti, B. A.; Trainor, D. A. J . Med. Chem.
996, 39, 619. (b) Kurdyumova, N. R.; Rozhko, L. F.; Ragulin, V. V.;
1
Tsvetkov, E. N. Russ. J . Gen. Chem. 1997, 67, 1852. (c) Kurdyumova,
N. R.; Rozhko, L. F.; Ragulin, V. V.; Tsvetkov, E. N. Russ. J . Gen. Chem.
a precursor to other biologically active compounds de-
This compound had been
previously synthesized in three steps, using the protect-
1
997, 67, 1857. Hypophosphite esters: (d) Gallagher, M. J .; Sussman,
J . Phosphorus 1975, 5, 91. (e) Maier, L. Helv. Chim. Acta 1973, 56,
89. (f) Caldwell, C. G.; Sahoo, S. P.; Polo, S. A.; Eversole, R. R.; Lanza,
1i,6c,20
veloped by Ciba-Geigy.
4
T. J .; Mills, S. G.; Niedzwiecki, L. M.; Izquierdo-Martin, M.; Chang,
B. C.; Harrison, R. K.; Kuo, D. W.; Lin, T.-Y.; Stein, R. L.; Durette, P.
L.; Hagmann, W. K. Bioorg. Med. Chem. Lett. 1996, 6, 323. (g)
Wroblewski, A. E.; Verkade, J . G. J . Am. Chem. Soc. 1996, 118, 10168.
(19) Dumond, Y. R.; Baker, R. L.; Montchamp, J .-L. Org. Lett. 2000,
2, 3341 and references cited. For example, PivOCH CH P(O)(OBu)H
2 2
was obtained in ca. 50% overall yield after esterification of the crude
acid, followed by chromatographic purification.
(18) Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25.

6
750 J . Org. Chem., Vol. 66, No. 20, 2001
Depr e` le and Montchamp
Ta ble 3. Ra d ica l Rea ction of Sod iu m Hyp op h osp h ite
avoiding the use of protection/deprotection sequences,
and the use of anhydrous hypophosphorous acid.
a
w ith F u n ction a lized Alk en es
Next, we explored the preparation of possible precur-
sors to P-heterocycles via tandem radical addition-polar
cyclizations (entries 8-11 of Table 3). Haloalkenes were
studied as substrates in the radical addition step. As
expected, some competing reduction was observed with
bromides (allyl bromide and 5-bromo-1-pentene), al-
though the desired product was formed as part of a
relatively complex product mixture. In contrast, chlorides
were tolerated, which with no doubt is due to the fact
that the reactions were run at ambient temperature. For
example, allyl chloride and chloroethyl vinyl ether gave
the corresponding adducts in 55-72 and 50-58% yields,
respectively (entries 8 and 9). Although heating the latter
intermediates with HMDS in toluene did produce some
amount of the corresponding heterocycles, these experi-
ments were not optimized and merely constituted a proof
of concept. Similarly, nonconjugated ketones are another
type of precursor amenable to tandem reactions, and
5
-hexen-2-one reacted to give the corresponding phos-
phinate salt in 94% yield (entry 10). Cyclization was not
tested because attempted extraction did not give the pure
ketone (although it was the major component in the
product mixture). Finally, o-(2-propenyl)phenyl trifluo-
romethanesulfonate21 reacted uneventfully to deliver the
corresponding phosphinate salt in 82% yield (entry 11),
which offers the possibility for subsequent Pd-catalyzed
cyclization. These experiments will be the basis for future
research.22
a
All reactions were conducted in reagent grade MeOH (0.2 M
in alkene) for 1.5-2 h, at room temperature in an open flask.
b
NaH2PO2/Et3B/alkene ) 2.5:1:1. Yield of phosphinate salt (M )
c
Na), as determined by integration of all the signals. Isolated by
extraction with aqueous KHSO4/EtOAc (see Experimental Sec-
tion). Monosubstituted phosphinic acid products (M ) H) were
>
90% pure. A 1 equiv portion of AcOH was added. e Side
d
products formed during attempted extraction.
On the basis of the data obtained through the reactions
of allyltributyltin and bromoalkenes, the simple radical
reduction of alkyl bromides was modeled with diethyl
ing group methodology devised in the same laboratories.
Unfortunately, allylamine did not react well with NaH
PO (0-20%) under the standard conditions. We reasoned
that it might be due to the formation of an amine-borane
complex which would inhibit the autooxidation of Et B.
2
-
2
-bromoethylphosphonate (eq 1). Not surprisingly, the
corresponding diethyl ethylphosphonate was obtained in
5% NMR yield (and a simple extraction delivered the
2
9
3
desired product in 87% isolated yield). In their experi-
ments, Oshima and co-workers employed a 10-fold excess
of hypophosphite salts and a 2-fold excess of Et B relative
3
to their aryl iodide substrates (aryl bromides were
unreactive).13 In our study with an alkyl bromide, both
reagents were used in significantly smaller quantities,
and in fact, reduction proceeded satisfactorily even with
To test our hypothesis, 1 equiv of acetic acid was added
to the reaction mixture prior to borane addition. We were
rewarded with an essentially quantitative yield of the
desired product (Table 3, entry 4). An additional run
supporting the initial hypothesis came from the treat-
ment of free allylamine with 2 equiv of Et
the adduct in 77% yield.
3
B to deliver
0
3
.1 equiv of Et B (66% yield). While this was not further
Similarly, the present methodology was applied to the
one-step preparation of an advanced intermediate em-
ployed by a Schering group for the synthesis of potential
inhibitors of pantothenate synthetase.1d Once again,
these researchers prepared (3-methoxycarbonyl-propyl)-
phosphinic acid using Ciba’s protection/reaction/depro-
tection sequence. With our methodology, methyl allyl-
investigated, since our focus remained on P-C bond
formation, this methodology provides a useful alternative
to Barton’s EPHP and related radical reductions initiated
thermally with AIBN.
(
21) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1988, 110,
557.
22) Although the Pd-catalyzed cross-coupling of phosphinate esters
1
acetate and allylacetic acid reacted with NaH
afford the corresponding phosphinate adducts in 98 and
5% yield, respectively (entries 6 and 7 of Table 3). This
2 2
PO to
(
is well established, aryl triflates have apparently not been used as
substrates in these reactions: (a) Xu, Y.; Zhang, J . Synthesis 1984,
9
7
(
78. (b) Xu, Y.; Li, Z.; Xia, J .; Guo, H.; Huang, Y. Synthesis 1983, 377.
c) Xu, Y.; Li, Z.; Xia, J .; Guo, H.; Huang, Y. Synthesis 1984, 781. (d)
Xu, Y.; Li, Z. Synthesis 1986, 240. (e) Xu, Y.; Xia, J .; Guo, H. Synthesis
novel reaction should therefore prove useful for the
preparation of a variety of functional intermediates,
1
1
986, 691. (f) Xu, Y.; Zhang, J . J . Chem. Soc., Chem. Commun. 1986,
606. (g) Xu, Y.; Wej, H.; Zhang, J .; Huang, G. Tetrahedron Lett. 1989,
(
20) Froestl, W.; Mickel, S. J .; Hall, R. G.; von Sprecher, G.; Diel, P.
30, 949. (h) Lei, H.; Stoakes, M. S.; Schwabacher, A. W. Synthesis 1992,
1255. (i) Schwabacher, A. W.; Zhang, S.; Davy, W. J . Am. Chem. Soc.
1993, 115, 6995. (j) Lei, H.; Stoakes, M. S.; Herath, K. P. B.; Lee, J .;
Schwabacher, A. W. J . Org. Chem. 1994, 59, 4206. (k) See also ref 6f.
J .; Strub, D.; Baumann, P. A.; Brugger, F.; Gentsch, C.; J aekel, J .;
Olpe, H.-R.; Rihs, G.; Vassout, A.; Waldmeier, P. C.; Bittiger, H. J .
Med. Chem. 1995, 38, 3297.

Synthesis of Phosphinic Acids and Esters
Overall, the Et B-promoted reaction of hypophosphite
J . Org. Chem., Vol. 66, No. 20, 2001 6751
Ta ble 4. Ra d ica l Rea ction of Meth yl a n d Bu tyl
Hyp op h osp h ites w ith Alk en esa
3
salts with olefins proceeds in high yield under mild
conditions. However, the isolated yields were significantly
lower due to the high aqueous solubility of many of the
products, and they have not been optimized. No attempt
was made to utilize continuous extraction techniques,
precipitation with adamantanamine, or ion-exchange
chromatography. Esterification of the products is the
most convenient isolation procedure, and we have already
reported a new protocol for the selective esterification of
monosubstituted phosphinic acids.19 Nonetheless, an
alternate direct method to prepare phosphinate esters
would be useful when sodium (or anilinium) phosphinates
are difficult to handle. With this idea in mind, we decided
to investigate the reactivity of alkyl hypophosphites in
radical reactions.
3
Hyp op h osp h ite Ester s. Since our Et B/air procedure
worked well with hypophosphite salts and was tolerant
of acid-sensitive functionalities, it occurred to us that
2
sensitive alkyl hypophosphites (ROP(O)H ) might be
employed as well. Alkyl hypophosphites are air and
moisture sensitive and thermally unstable. The latter
property precludes their use in AIBN-initiated reactions
since, for example, methyl hypophosphite decomposes in
about an hour at 80 °C.2
2h
To the best of our knowledge, a single report describes
2
3
the radical reaction of an alkyl hypophosphite. Butyl
hypophosphite was reacted with allyl acetate, in a sealed
tube at 130-140 °C for 10 h in the presence of di-tert-
butyl peroxide, to produce butyl bis-(3-acetoxypropyl)-
phosphinate in 25% yield. The extent of decomposition
a
All reactions were conducted for 1.5-2 h, at room temperature
b
in an open flask. See Experimental Section for details. Yield of
phosphinate ester, as determined by integration of all the signals.
Isolated by extraction with aqueous KHSO4/EtOAc followed by
c
d
chromatography (see Experimental Section). TBDMS ether, 1:1
2
3
mixture of diastereoisomers. e Desilylated during workup, 1:1
mixture of diastereoisomers. A small amount of contaminating silyl
ether is also present. f Obtained in ca. 90% purity after extraction.
under such conditions was not discussed.
2
4
Since Fitch’s original report in 1964, alkyl hypophos-
phites (ROP(O)H ) have seldom been used. A few excep-
2
tions can be found, for example, in the works of Gallagh-
er, Stawinski, and Schwabacher, among others.25 There
are two major methods to prepare alkyl hypophosphi-
hypophosphite (MeOP(O)H
formate method and then reacted with 1-octene at room
temperature with 1 equiv of Et B in an open flask. Once
again, a rapid reaction took place and the desired ester
was formed as the major product. A detailed analysis of
this reaction requires prior discussion of several impor-
2
) was prepared by the ortho-
tes: (1) esterification of anhydrous H
3
PO
2
with orthofor-
PO with
3
mates (R ) Me, Et)24 and (2) esterification of H
3
2
an alcohol with azeotropic removal of water (Dean-Stark
trap).26 Both methods were employed in this study. Other
methods27 such as esterification with diazoalkanes or
triethyloxonium tetrafluoroborate are much less conve-
nient and were not considered.
Room Tem p er a tu r e Ra d ica l Rea ction of Meth yl
Hyp op h osp h ite (En tr ies 1-6 of Ta ble 4). Methyl
tant parameters. First, 2 equiv of (MeO)
ployed, because crystalline anhydrous H PO
inconvenient to prepare, and excess orthoformate re-
moves the traces of moisture remaining in H PO after
3
CH was em-
3
2
is relatively
3
2
high vacuum concentration of the commercial (50% by
wt) aqueous solution. The resulting crude reaction mix-
ture was directly used in the following step. Second, the
yield of methyl hypophosphite under these conditions is
(23) Aleksandrova, I. A.; Ufimtseva, L. I. Bull. Acad. Sci. USSR,
Div. Chem. Sci. 1971, 6, 1218.
(
24) Fitch, S. J . J . Am. Chem. Soc. 1964, 86, 61.
(25) For examples on the use of hypophosphite esters, see: (a)
3
1
usually 85-90% ( P NMR) and never exceeded 90% in
Ivanov, B. E.; Kudryavtseva, L. A. Bull. Acad. Sci., USSR 1968, 7,
1
1
544. (b) Ivanov, B. E.; Kudryavtseva, L. A. Bull. Acad. Sci., USSR
967, 7, 1447. (c) Vysotskii, V. I.; Skobun, A. S.; Tilichenko, M. N. J .
our hands, yet in the following discussion the number of
equivalents refers to the total amount of phosphorus (H
3
-
Gen. Chem. USSR 1979, 49, 1721. (d) Livantsov, M. V.; Prishchenko,
A. A.; Lutsenko, I. F. J . Gen. Chem. USSR 1986, 56, 2195. (e)
Livantsov, M. V.; Prishchenko, A. A.; Lutsenko, I. F. J . Gen. Chem.
USSR 1986, 56, 1976. (f) Natchev, I. A. Phosphorus, Sulfur 1988, 37,
PO starting material) and not that of methyl hypophos-
2
phite formed. Third, the reaction concentration for the
radical step was controlled by adding anhydrous dioxane
1
33. (g) Natchev, I. A. Liebigs Ann. Chem. 1988, 861. (h) Yamagishi,
T.; Yokomatsu, T.; Suemune, K.; Shibuya, S. Tetrahedron 1999, 55,
2125. (i) Baylis, E. K. Tetrahedron Lett. 1995, 36, 9389. (j) Grice, I.
(although other solvents, including methanol, can also
1
be used for this purpose).
The results of various runs have been collected in Table
4 (entries 1-6). The H PO and Et B equivalents are the
3 2 3
two key variables that are crucial to obtain good yields
of the desired phosphinate product (some of these experi-
ments are summarized in Supporting Information).
D.; Harvey, P. J .; J enkins, I. D.; Gallagher, M. J .; Ranasinghe, M. G.
Tetrahedron Lett. 1996, 37, 1087. (k) Gallagher, M. J .; Honegger, H.
J . Chem. Soc., Chem. Commun. 1978, 54. (l) Schwabacher, A. W.;
Stefanescu, A. D. Tetrahedron Lett. 1996, 37, 425. (m) Devedjiev, I.;
Ganev, V.; Stefanova, R.; Borisov, G. Phosphorus Sulfur 1987, 31, 7.
(n) Gallagher, M. J .; Ranasinghe, M. G. Phosphorus, Sulfur Silicon
Relat. Elem. 1996, 115, 255. (o) Gallagher, M. J .; Ranasinghe, M. G.
J . Org. Chem. 1996, 61, 436. (p) J ankowska, J .; Cieslak, J .; Kraszewski,
A.; Stawinski, J . Tetrahedron Lett. 1997, 38, 2007. (q) See also refs
1
7d-g, 22h-j, and 27b.
26) Nifant’ev, E. E.; Levitan, L. P. J . Gen. Chem. USSR 1965, 35,
62.
(27) (a) Pinnick, H. W.; Reynolds, M. A. Synth. Commun. 1979, 9,
535. (b) Stawinski, J .; Thelin, M.; Westman, E.; Zain, R. J . Org. Chem.
1990, 55, 3503.
(
7

6
752 J . Org. Chem., Vol. 66, No. 20, 2001
Depr e` le and Montchamp
Interestingly, alkyl hypophosphites appear much more
prone to H-abstraction resulting in more efficient chain
reactions than of the salts, and consistently higher yields
h in a Dean-Stark apparatus under N
concentration in phosphorus was ∼1 M. Since the con-
centration of aqueous H PO in vacuo prior to esterifi-
2
. The final
3
2
were obtained with as little as 0.1-0.2 equiv of Et
diminished amount of alkyl hypophosphite results in
significantly lower yields; therefore, 3 equiv of MeOP-
3
B. A
cation gave similar results, the former more practical
direct procedure was adopted routinely. Under these
conditions, the yield of BuOP(O)H
90%, the remainder being H PO . After being cooled, the
2
was typically 80-
(O)H
2
was used per olefin (assuming quantitative esteri-
3
2
fication). The crude reaction mixtures are always much
more complex than those with the hypophosphite salts,
due to the fact that the formation and decomposition of
reaction solution is used directly for the radical reaction
(alkene concentration ) ∼0.3 M).
Results (entries 7-10 of Table 4) of the radical reaction
MeOP(O)H
2
is responsible for several side products, as
with BuOP(O)H
2
were similar to the ones observed with
2
4,28
31
previously reported in the literature.
For this reason,
MeOP(O)H , except that the crude P NMR spectra were
2
the yields determined by 31P NMR are somewhat less
accurate than those determined with hypophosphite salts
and should only be used as a qualitative measurement
for comparison between different runs. Nonetheless, the
desired ester was always the major product of P-C bond
formation, although some of the corresponding phos-
phinic acid was a common contaminant.29 Purification
was also difficult. Extractive workup can be used to
simpler, with less side products being present in the
reaction mixtures. In addition, isolated yields were
typically higher, possibly because the butyl phosphinates
are more robust during chromatography. When menthyl
2
hypophosphite (MenOP(O)H ) was used, no induction
(“desymmetrization” at phosphorus) was observed. This
might not be surprising since the chirality is far away
from the diastereotopic phosphinylidene hydrogens. None-
theless, this type of approach might still be adapted to
the asymmetric synthesis of new carbon or phosphorus
chiral centers, and the ester group may ultimately be
designed to increase diastereotopicity. This and the
development of a low-temperature protocol are the direc-
tions we will be actively following with this project.
The radical reactions of alkyl hypophosphites and
hypophosphite salts are complementary, and the choice
of one vs the other is dictated by the olefinic substrate.
On one hand, hypophosphite salts provide the highest
yields and can be reacted without any special precaution
2 3 2
hydrolyze MeOP(O)H and remove the H PO formed, but
here again, the polarity of the phosphinate esters causes
loss of material in the aqueous phase. Direct purification
by chromatography could also be used, but slow hydroly-
sis of the ester on silica gel can decrease the isolated
yield.
Ethyl hypophosphite24 reacted similarly (see table in
Supporting Information).
Room Tem p er a tu r e Ra d ica l Rea ction of Bu tyl
Hyp op h osp h ite (En tr ies 7-10 of Ta ble 4). Butyl
2
hypophosphite (BuOP(O)H ) was obtained by esterifica-
(moisture tolerant) but require 0.5-1.0 equiv of orga-
tion of hypophosphorous acid with butanol under azeo-
tropic water removal.26 It was chosen as a representative
noborane initiator and a separate esterification step if
the ester is desired. On the other hand, alkyl hypophos-
phites directly deliver a phosphinate ester even with a
example of the direct esterification method pioneered by
Nifant’ev.26 In the literature, the conditions for this
reaction (concentration, reaction time, scale, amount, and
nature of the alcohol employed) have not been studied
in great detail. The scope of alcohols which can be
employed has apparently not been investigated beyond
3
catalytic amount of Et B and circumvent the acidification
step usually required prior to esterification. In the case
of highly sensitive compounds, the latter method remains
advantageous even if the yields of radical addition are
lowered due to the competing formation of alkylphos-
the simple alkyls (i-Pr, Bu, Hex, n-C12H25) and certain
2
9
3 2
phinic acid from residual H PO .
polyols. Therefore, after our own limited investigation,
we settled on a “standard” set of conditions. As expected,
temperature (i.e., the solvent employed), reaction time,
concentration, and number of equivalents of alcohol are
all important factors. The first two interrelated param-
eters are especially important, as the ester that is formed
can decompose over time. The reaction could be moni-
tored by NMR, but in all the runs that were conducted,
we never found conditions which provided quantitative
formation of the alkyl hypophosphite. We selected cyclo-
hexane as the solvent to replace toxic benzene while
maintaining the same reaction temperature. (Although
this may not be a widely known fact, cyclohexane is an
excellent benzene replacement in azeotropic distillation
and possesses properties essentially identical to that of
benzene, including azeotropic composition.) Butyl hypo-
phosphite was thus prepared by directly refluxing a
mixture of a commercial aqueous solution of hypophos-
phorous acid and butanol (2 equiv) in cyclohexane for 4-6
Methodological advances for the preparation of hypo-
phosphite esters would further increase the synthetic
value of this reaction, as both yields and isolation
procedures might improve. Indeed, we recently developed
a new esterification reaction which consistently affords
3
0
almost quantitative yields of alkyl hypophosphites.
Under these conditions, the radical reactions proceed
with significantly higher yields, particularly with methyl
hypophosphite, and little or no phosphinic acid is pro-
duced. For example,30 N-tert-butyl-allylcarbamate reacted
with methyl hypophosphite to provide the corresponding
methyl phosphinate in 60% isolated yield (eq 2, compare
to entry 3 of Table 4).
(
28) (a) Gallagher, M. J .; Honegger, H. Tetrahedron Lett. 1977, 34,
987. (b) Gallagher, M. J .; Honegger, H. Aust. J . Chem. 1980, 33, 287.
c) Gallagher, M. J .; Garbutt, R.; Hua, L. Y.; Lee, G. H. Phosphorus,
Sulfur Silicon Relat. Elem. 1993, 75, 201.
29) As shown in Table 1, entry 18, H PO
under these conditions. Thus, residual H PO
hypophosphite solution, leads to monosubstituted phosphinic acid.
2
(
(
3
2
also reacts with alkenes
, present in the alkyl
3
2
(30) Depr e` le, S.; Montchamp, J .-L. J . Organomet. Chem., in press.

Synthesis of Phosphinic Acids and Esters
J . Org. Chem., Vol. 66, No. 20, 2001 6753
Ch a r t 1. 31P NMR Ch em ica l Sh ift P r ed iction of P h osp h in a te Der iva tives
Con clu sion
Hyp op h osp h or ou s Der iva tives. Sodium hypophosphite
hydrate and aqueous hypophosphorous acid (50% by wt) were
obtained from Aldrich and used as received. Before the
reaction, hypophosphorous acid was concentrated in vacuo on
a rotary evaporator at room temperature for 20-30 min.
Anilinium hypophosphite was prepared as previously described
by us.7 Triethylammonium hypophosphite was prepared
according to ref 27b. Ammonium hypophosphite was prepared
as described in ref 4f. EPHP was purchased from Aldrich and
used as received.
In conclusion, we have found a novel and practical
method for the formation of P-C bonds under mild
conditions. Functional groups are well tolerated, and
previously inaccessible compounds have been prepared.
For hypophosphite salts, the yields of adducts are usually
excellent and the crude reaction mixtures are very clean,
but isolation can be cumbersome particularly with rela-
,30
3
tively polar alkenes, and at least 0.5 equiv of Et B is
Solven ts. Reagent grade methanol was used in all reactions
involving hypophosphite salts (Tables 1-3). Anhydrous sol-
vents were prepared as follows: dioxane was dried over
required for reproducible results. An alternative protocol
employs highly sensitive alkyl hypophosphites to directly
produce a monosubstituted phosphinate ester and has
the advantage of requiring only a catalytic quantity of
borane while producing a more easily handled phosphi-
nate ester. Nonetheless, difficulties still exist in the
isolation of the products, and the yields of the radical
reaction are intrinsically lower than with the hypophos-
phite salts. A cleaner and more convenient preparation
activated 4A molecular sieves and stored under N
and triethylamine were distilled from calcium hydride and
stored under N over activated 4A molecular sieves; benzene
was distilled, immediately before use, from calcium hydride
under N
2
; pyridine
2
2
.
31
P NMR Yield Mea su r em en ts. NMR yields were deter-
31
mined by integration of all the P signals. During our studies
of phosphinates and related compounds, we realized that a
chart for the prediction of 31P chemical shifts of salts, acids,
and esters, based on the knowledge of one of these chemical
shifts, would be useful to us and others. On the basis of our
data, we compiled Chart 1 which, surprisingly, is applicable
over a wide range of concentrations and solvents (within 1 or
of hypophosphite esters would therefore be desirable in
order to further develop this methodology.30 Ultimately,
the choice between hypophosphorous ester or salt will
be dictated by the particular reaction under study. The
novel reaction disclosed herein opens up a number of
research avenues. Future work will focus on further
optimization of the methodology, particularly in tandem
processes, and on the development of an asymmetric
version.
2
ppm). For example, if the chemical shift of OctP(O)(OBu)H
is known at 38.5 ppm, one could predict the following chemical
shifts: ethyl ester at 38.5 + 1 ) 39.5 (experimental value )
39.0); methyl ester at 38.5 + 4 + 1 ) 43.5 (experimental value
) 42.6); acid at 38.5 - 2 ) 36.5 (experimental value ) 37.8);
anilinium salt at 38.5 - (2 + 5) ) 31.5 (experimental value )
3
2
1.0); sodium salt at 38.5 - 10 ) 28.5 (experimental value )
9).
Exp er im en ta l Section
1
Room Tem p er a tu r e Ra d ica l Rea ction of Sod iu m Hy-
Gen er a l Ch em istr y. H NMR spectra were recorded on a
Varian XL-300 spectrometer. Chemical shifts for 1H NMR
spectra are reported (in ppm) relative to internal tetrameth-
p op h osp h ite: Rep r esen ta tive P r oced u r e (Ta bles 1-3).
To a solution of NaH PO O (5 mmol) and alkene (2 mmol)
2
2
‚H
2
1
3
in methanol (10 mL) was added Et B (1.0 M, 2 mL, 2 mmol),
ylsilane (Me
spectra were recorded at 75 MHz. Chemical shifts for C NMR
spectra are reported (in ppm) relative to CDCl (δ ) 77.0 ppm).
P NMR spectra were recorded at 121 MHz, and chemical
4
Si, δ ) 0.00 ppm) with CDCl
3
as solvent. C NMR
3
1
3
at room temperature in an open reaction vessel. The solution
was stirred at room temperature for 2 h. 31P NMR analysis of
the crude reaction mixture was used to calculate the NMR
yield at that time. The reaction mixture was concentrated on
a rotary evaporator, and the residue was partitioned between
3
3
1
shifts are reported (in ppm) relative to external 85% phospho-
ric acid (δ ) 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).
Ethyl acetate/hexanes mixtures were used as the eluent for
chromatographic purifications. TLC plates were visualized by
immersion in anisaldehyde stain (by volume: 93% ethanol,
.5% sulfuric acid, 1% acetic acid, and 2.5% anisaldehyde)
followed by heating. Organic solutions of products were dried
over MgSO and filtered.
4
aqueous KHSO and EtOAc. The aqueous layer was extracted
twice with EtOAc, and the combined organic layers were dried
and concentrated to afford the crude phosphinic acid (typically
in greater than 90% purity). The same procedure was em-
ployed with other hypophosphite salts.
1
0a
1H NMR
3
Octylp h osp h in ic Acid (Ta ble 2, En tr y 1).
(CDCl ) δ 10.72 (bs, 1H), 7.08 (d, J ) 540 Hz, 1H), 1.1-1.80
(m, 16H), 0.88 (t, J ) 6 Hz, 3H); C NMR (CDCl ) δ 31.6, 30.3
3
1
3
4
3
Rea gen ts a n d Solven ts. Unless otherwise noted, reagents
were used as received. 3,3-Dimethyl-2-{[(1,1-dimethylethyl)-
dimethylsilyl]oxy}-1-butene was prepared as follows: TBDM-
SOTf (2.0 mL, 8.7 mmol) was added neat to a solution of
(d, J PCCC ) 16 Hz), 29.1 (d, J PC ) 94 Hz), 29.0, 28.9, 22.5, 20.6
(d, J PCC ) 3 Hz), 14.0; 31P NMR (CDCl
) δ 37.8 (dt, J P-H )
3
540, 14 Hz).
Decylp h osp h in ic Acid (Ta ble 2, En tr y 2).1g,10a 1H NMR
pinacolone (0.833 g, 8.3 mmol) and anhydrous Et
3
N (1.8 mL,
(CDCl
(m, 18H), 0.88 (t, J ) 6 Hz, 3H); C NMR (CDCl
(d, J PCCC ) 16 Hz), 29.2 (d, J PC ) 94 Hz), 29.5, 29.3, 29.2, 29.1,
22.6, 20.5 (d, J PCC ) 3 Hz), 14.1; 31P NMR (CDCl
) δ 38.8 (dt,
P-H ) 537 Hz).
4-P h en ylbu tylp h osp h in ic Acid (Ta ble 2, En tr y 3).1g 1H
NMR (CDCl ) δ 11.40 (bs, 1H), 7.04 (d, J ) 540 Hz, 1H), 7.0-
7.45 (m, 5H), 2.61 (t, J ) 7 Hz, 2H), 1.5-2.0 (m, 6H); C NMR
(CDCl ) δ 144.2, 128.3, 125.8, 35.3, 32.1 (d, J PCCC ) 16 Hz),
3
) δ 10.39 (bs, 1H), 7.05 (d, J ) 537 Hz, 1H), 1.15-1.90
13
1
3 mmol) in anhydrous benzene (20 mL), at room temperature
3
) δ 31.8, 30.4
2
under N . The dark reaction mixture was refluxed for 4 h.
Water and ether were added to the cool reaction mixture. The
organic layer was washed with 0.5 N aqueous HCl, saturated
aqueous CuSO , water, and brine. Concentration afforded the
4
enol ether in quantitative yield. Its spectral data was identical
3
J
3
1
3
to that reported in: Bach, T.; J o¨ dicke, K. Chem. Ber. 1993,
1
26, 2457.
3

6
754 J . Org. Chem., Vol. 66, No. 20, 2001
Depr e` le and Montchamp
2
9.0 (d, J PC ) 94 Hz), 20.3 (d, J PCC ) 3 Hz), 14.1; 31P NMR
Met h yl [3,3-d im et h yl-2-h yd r oxy-b u t yl]p h osp h in a t e
(Ta ble 4, En tr y 4). (1:1 mixture of diastereoisomers). H NMR
1
(CDCl
3
) δ 37.5 (dt, J P-H ) 540 Hz).
1
5
-Hexen ylp h osp h in ic Acid (Ta ble 2, En tr y 4). H NMR
(CDCl
3
) δ 7.19 (d, J ) 541 Hz, 1H), 7.17 (d, J ) 540 Hz, 1H),
(
CDCl ) δ 10.89 (bs, 1H), 7.02 (d, J ) 530 Hz, 1H), 5.65-5.9
3
3.78 (d, J ) 12 Hz, 6H), 3.7-3.9 (m, 2H), 2.05-2.25 (m, 2H),
1
3
(m, 1H), 4.9-5.1 (m, 2H), 1.95-2.25 (m, 2H), 1.35-1.90 (m,
3
1.8-2.0 (m, 2H), 0.90 (s, 9H), 0.89 (s, 9H); C NMR (CDCl )
1
3
6
1
H); C NMR (CDCl
3
) δ 138.0, 114.9, 33.2, 29.6 (d, J PCCC
)
δ 74.2, 74.1, 52.8 (d, J POC ) 7 Hz), 52.5 (d, J POC ) 7 Hz), 36.2,
36.1, 34.2 (d, J PC ) 94 Hz), 34.0 (d, J PC ) 94 Hz), 25.9, 25.8;
3
1
6 Hz), 29.2 (d, J PC ) 94 Hz), 20.3; P NMR (CDCl
3
) δ 37.8
3
1
(dm, J P-H ) 530 Hz).
P NMR (CDCl
) 537 Hz).
3
) δ 41.4 (dm, J P-H ) 538 Hz), 40.4 (dm, J P-H
Cycloh exylp h osp h in ic Acid (Ta ble 2, En tr y 8).1 1H
0a
1
NMR (CDCl
3
) δ 12.13 (bs, 1H), 6.81 (d, J ) 532 Hz, 1H), 1.6-
Meth yl cycloh exylp h osp h in a te (Ta ble 4, En tr y 5). H
1
3
2
J
J
.15 (m, 7H), 1.05-1.55 (m, 4H); C NMR (CDCl
3
) δ 37.2 (d,
NMR (CDCl ) δ 6.80 (dd, J ) 521, 2 Hz, 1H), 3.78 (d, J ) 11
3
3
1
13
PC ) 96 Hz), 25.7, 25.5, 23.8; P NMR (CDCl
P-H ) 535 Hz).
3
) δ 41.9 (dm,
3
Hz, 3H), 1.6-2.0 (m, 6H), 1.15-1.5 (m, 5H); C NMR (CDCl )
δ 52.8 (d, J POC ) 8 Hz), 37.4, 36.1, 35.7 (d, J PC ) 89 Hz), 25.0-
(
2-Tr im eth ylsilyl)eth ylp h osp h in ic Acid (Ta ble 2, En -
26.2 (multiple peaks, could not be deconvoluted), 23.9 (d, J PCC
1
31
tr y 12). H NMR (CDCl
Hz, 1H), 1.5-1.75 (m, 2H), 0.3-0.4 (m, 2H), 0.00 (s, 9H);
NMR (CDCl ) δ 22.6 (d, J PC ) 92 Hz), 5.9 (d, J PCC ) 7 Hz),
2.3; P NMR (CDCl ) δ 41.1 (dm, J P-H ) 540 Hz).
2-P iva loyloxy)eth ylp h osp h in ic Acid (Ta ble 3, En tr y
3
) δ 11.68 (bs, 1H), 6.99 (d, J ) 540
) 6 Hz); P NMR (CDCl ) δ 46.7 (d, J P-H ) 521 Hz).
3
1
3
1
C
Meth yl octylp h osp h in a te (Ta ble 4, En tr y 6). H NMR
(CDCl ) δ 7.05 (dt, J ) 529, 2 Hz, 1H), 3.78 (d, J ) 12 Hz,
3H), 1.5-1.85 (m, 4H), 1.2-1.45 (m, 10H), 0.88 (t, J ) 7 Hz,
3H); 31P NMR (CDCl
) δ 42.6 (dq, J P-H ) 528, 14 Hz).
(2) Bu tyl Ester s. A flask containing H PO (50% aqueous
3
3
3
1
-
3
(
3
1
1
4
). H NMR (CDCl
3
) δ 9.60 (bs, 1H), 7.20 (d, J ) 560 Hz, 1H),
3
2
1
3
.25-4.45 (m, 2H), 2.05-2.3 (m, 2H), 1.20 (s, 9H); C NMR
solution by wt, 33 mmol) and butanol (6 mL, 66 mmol) in
cyclohexane (reagent grade, 40 mL) was equipped with a
Dean-Stark trap prefilled with cyclohexane and fitted with a
(
(
CDCl
CDCl
3
) δ 60.0, 38.7, 29.6 (d, J PC ) 94 Hz), 27.1; 31P NMR
) δ 30.8 (dm, J P-H ) 560 Hz).
3
(
3-(ter t-bu toxyca r bon yla m in o)p r op yl)p h osp h in ic Acid
condenser. The solution was refluxed under N
then cooled to room temperature. The alkene (11 mmol) and
Et B (1.0 M, 1.1-11 mL, 1.1-11 mmol) were successively
added to the open flask, and the resulting solution was stirred
at room temperature for 2 h. EtOAc and aqueous KHSO were
added, and the resulting organic layer was washed with
saturated aqueous NaHCO and then with brine. Drying and
2
for 4-6 h and
1
(
Ta ble 3, En tr y 3). H NMR (CDCl
3
) δ 7.37 (d, J ) 558 Hz,
1
3
1
H), 3.1-3.35 (bm, 2H), 1.65-1.95 (bm, 4H), 1.44 (s, 9H);
C
3
NMR (CDCl ) δ 156.1, 79.0, 40.4 (m), 28.2, 26.4 (d, J PC ) 95
Hz), 21.3; P NMR (CDCl
3
3
1
3
) δ 38.5 (dm, J P-H ) 558 Hz).
4
(
3-Am in op r op yl)p h osp h in ic Acid (CGP 27492, Ta ble 3,
6
c 1
En tr y 4). H NMR (D
3
)
2
O) δ 7.13 (d, J ) 540 Hz, 1H), 3.1-
3
3
1
.3 (bm, 2H), 1.7-2.2 (bm, 4H); P NMR (D
2
O) δ 36.5 (d, J P-H
concentration afforded the crude butyl phosphinate, which was
purified by chromatography over silica gel.
540 Hz).
3-Ch lor op r op yl)p h osp h in ic Acid (Ta ble 3, En tr y 8).
) δ 12.07 (bs, 1H), 7.14 (d, J ) 549 Hz, 1H),
1
9
(
Bu tyl (4-p h en ylbu tyl)p h osp h in a te (Ta ble 4, En tr y 7).
1
1
H NMR (CDCl
3
H NMR (CDCl
3
) δ 7.1-7.3 (m, 5H), 7.05 (d, J ) 528 Hz, 1H),
1
3
3
4
.63 (t, J ) 6 Hz, 2H), 1.8-2.2 (m, 4H); C NMR (CDCl
5.1 (d, J PCCC ) 18 Hz), 27.0 (d, J PC ) 95 Hz), 24.4; 31P NMR
) δ 36.5 (dm, J P-H ) 549 Hz).
3-(o-T r i flu o r o m e t h a n e s u lfo n y l)p h e n y lp r o p y l)-
3
) δ
3.9-4.2 (m, 2H), 2.62 (t, J ) 7 Hz, 2H), 1.5-1.85 (m, 6H),
13
1.25-1.45 (m, 2H), 0.93 (t, J ) 7 Hz, 3H); C NMR (CDCl ) δ
3
(CDCl
3
141.4, 128.9, 125.6, 65.8 (d, J POC ) 7 Hz), 35.1, 32.1 (d, J PCCCC
(
) 6 Hz), 31.8 (d, J PCCC ) 16 Hz), 28.3 (d, J PC ) 94 Hz), 20.1 (d,
1
31
p h osp h in ic Acid (Ta ble 3, En tr y 11). H NMR (CDCl
1
3
) δ
J
PCC ) 3 Hz), 18.5, 13.3; P NMR (CDCl
3
) δ 39.5 (d, J P-H
)
0.36 (bs, 1H), 7.2-7.4 (m, 4H), 7.08 (d, J ) 545 Hz, 1H), 2.81
528 Hz).
Bu tyl cycloh exylp h osp h in a te (Ta ble 4, En tr y 8). 1
NMR (CDCl
1.6-2.0 (m, 8H), 1.2-1.5 (m, 7H), 0.95 (t, J ) 7 Hz, 3H);
NMR (CDCl
1
3
(
1
t, J ) 7 Hz, 3H), 1.6-2.0 (m, 4H); C NMR (CDCl
3
) δ 147.9,
H
33.5, 131.2, 128.5, 128.3, 121.4, 118.5 (q, J CF ) 320 Hz), 30.3
3
) δ 6.82 (dd, J ) 518, 2 Hz, 1H), 3.9-4.2 (m, 2H),
3
1
13
(
d, J PCCC ) 17 Hz), 28.5 (d, J PC ) 94 Hz), 20.9; P NMR (CDCl
3
)
C
δ 37.0 (d, J P-H ) 550 Hz).
Room Tem p er a tu r e Ra d ica l Rea ction of Alk yl Hyp o-
p h osp h it es: R ep r esen t a t ive P r oced u r es (Ta b le 4). (1)
3
) δ 65.9 (d, J POC ) 7 Hz), 37.0 (d, J PC ) 96 Hz),
3
1
3
32.3, 32.2, 25.7(2), 25.5, 24.1, 24.0, 18.7, 13.5; P NMR (CDCl )
δ 44.3 (d, J P-H ) 519 Hz).
Bu tyl (2-a cetoxy)eth ylp h osp h in a te (Ta ble 4, En tr y 9).
Meth yl Ester s. H
mmol) was concentrated in vacuo for 20-30 min at room
temperature. (MeO) CH (1.3 mL, 12 mmol) was added under
, and the solution was stirred for 1-2 h at room tempera-
ture. Anhydrous dioxane (5 mL), the alkene (2 mmol), and then
Et
3
PO
2
(50% aqueous solution by wt, 0.8 g, 6
1
H NMR (CDCl
3
) δ 7.22 (d, J ) 546 Hz, 1H), 4.3-4.45 (m, 2H),
3
3.95-4.25 (m, 2H), 2.1-2.25 (m, 2H), 2.07 (s, 3H), 1.6-1.75
1
3
N
2
(m, 2H), 1.3-1.45 (m, 2H), 0.95 (t, J ) 7 Hz, 3H); C NMR
(CDCl
3
) δ 170.2, 66.2 (d, J P3OC ) 6 Hz), 57.2, 32.0, 28.5 (d, J PC
1
3
B (1.0 M, 0.2-2.0 mL, 0.2-2.0 mmol) were successively
) 94 Hz), 20.4, 18.4, 13.2; P NMR (CDCl
3
) δ 33.5 (dm, J P-H
added to the open flask. The resulting solution was stirred at
room temperature for 2 h. The reaction mixture was concen-
trated on a rotary evaporator, and then aqueous KHSO
EtOAc were added. The aqueous layer was extracted twice
with EtOAc, and the combined organic layers were washed
successively with saturated aqueous NaHCO
Drying and concentration afforded the crude methyl phosphi-
nate, which was purified by chromatography over silica gel.
The same protocol could also be scaled up to 20-30 mmol of
alkene.
) 547 Hz).
Bu tyl (3-(o-Tr iflu or om eth a n esu lfon yl)p h en ylp r op yl)-
1
4
and
3
p h osp h in a te (Ta ble 4, En tr y 10). H NMR (CDCl ) δ 7.2-
7.4 (m, 4H), 7.10 (d, J ) 531 Hz, 1H), 3.9-4.2 (m, 2H), 2.84 (t,
J ) 8 Hz, 3H), 1.7-2.05 (m, 4H), 1.6-1.7 (m, 2H), 1.3-1.5
and brine.
(m, 2H), 0.94 (t, J ) 7 Hz, 3H); 13C NMR (CDCl
) δ 147.8,
3
3
133.4, 131.1, 128.5, 128.3, 121.4, 118.4 (q, J CF ) 320 Hz), 66.2
(d, J POC ) 7 Hz), 32.3, 30.3 (d, J PCCC ) 16 Hz), 28.1 (d, J PC
)
)
3
1
94 Hz), 20.9, 18.6, 13.4; P NMR (CDCl
531 Hz).
3
) δ 38.2 (dm, J P-H
Met h yl (2-P iva loyloxy-et h yl)p h osp h in a t e (Ta ble 4,
Ra d ica l Red u ction (eq 1). To a solution of NaH
2
PO ‚H
2
2
O
1
En tr y 1). H NMR (CDCl
3
) δ 7.20 (d, J ) 548 Hz, 1H), 4.25-
(5 mmol) and diethyl 2-bromoethylphosphonate (2 mmol) in
methanol (10 mL) was added Et B (1.0 M, 2 mL, 2 mmol), at
4
(
3
J
.45 (m, 2H), 3.83 (d, J ) 12 Hz, 3H), 2.15-2.35 (m, 2H), 1.21
3
1
3
s, 9H); C NMR (CDCl
3
) δ 177.6, 57.2, 52.7 (d, J POC ) 7 Hz),
room temperature in air. The solution was stirred at room
3
1
31
8.4, 28.5 (d, J PC ) 94 Hz), 26.8; P NMR (CDCl
P-H ) 548 Hz).
Met h yl (4-p h en ylb u t yl)p h osp h in a t e (Ta b le 4, E n t r y
3
) δ 36.4 (dm,
temperature for 2 h (95% yield by P NMR analysis). The
reaction mixture was concentrated under reduced pressure.
Ether and water were added. The organic layer was dried and
concentrated to afford diethyl ethylphosphonate, identical to
the commercially available material.
9
1
2
(
).1 H NMR (CDCl
3
) δ 7.02 (dt, J ) 530, 2 Hz, 1H), 7.1-7.3
m, 5H), 3.75 (d, J ) 12 Hz, 3H), 2.63 (t, J ) 7 Hz, 2H), 1.55-
.85 (m, 6H); C NMR (CDCl
1
3
1
5
)
3
) δ 141.4, 128.2, 128.1, 125.7,
Met h yl (3-(ter t-b u t oxyca r b on yla m in o)p r op yl)p h os-
2.6 (d, J POC ) 7 Hz), 35.2, 31.9 (d, J PCC ) 15 Hz), 28.2 (d, J PC
93 Hz), 20.1 (d, J PCCC ) 3 Hz); P NMR (CDCl
p h in a te (eq 2).30 Concentrated H
3
PO
solution by wt, 0.681 g, 5.1 mmol) was dissolved in CH
(HPLC grade, 10 mL), and the reaction flask was equipped
2
(initially 50% aqueous
3
1
3
) δ 42.2 (d,
3
CN
J
P-H ) 530 Hz).

Synthesis of Phosphinic Acids and Esters
with a reflux condenser and placed under N
J . Org. Chem., Vol. 66, No. 20, 2001 6755
2
. Trifluoroacetic
(CDCl
3
) δ 155.9, 52.8 (d, J POC ) 7 Hz), 40.5 (d, J PCCC ) 6 Hz),
3
1
acid (0.39 mL, 5.1 mmol) and 3-aminopropyltrimethoxysilane
0.90 mL, 5.1 mmol) were then added successively at room
40.4, 28.3, 25.8 (d, J PC ) 94 Hz), 21.4 (d, J PCC ) 3 Hz);
NMR (CDCl ) δ 40.5 (dm, J P-H ) 521 Hz).
3
P
(
temperature. An exothermic reaction took place immediately,
and the mixture was heated to reflux. After 2 h, the reaction
mixture was allowed to cool to room temperature. The flask
was open to air, N-tert-butyl-allylcarbamate (0.326 g, 2.1
mmol) was added, followed by triethylborane (1 M in hexanes,
Ack n ow led gm en t. This work was supported by
grants from The Robert A. Welch Foundation (P-1435)
and The Petroleum Research Fund, administered by the
ACS (34334-G1). We thank J . Achkar (Purdue Univer-
sity) for helpful discussions.
2
.0 mL, 2 mmol), and the heterogeneous mixture was stirred
in air at room temperature for 2 h. The crude reaction mixture
94% NMR yield) was treated with EtOAc and aqueous
KHSO . The organic layer was washed successively with
saturated aqueous NaHCO
(
4
Su ppor tin g In for m ation Available: Representative spec-
troscopic data and table summarizing the study of reaction
parameters for the radical reaction of methyl and ethyl
hypophosphites. This material is available free of charge via
the Internet at http://pubs.acs.org.
3
(1×) and brine (1×). Drying,
concentration, and purification by radial chromatography (4
mm thickness, EtOAc/hexane 1:1, v/v, EtOAc) afforded the
1
adduct (0.296 g, 60%) as a colorless oil: H NMR (CDCl
7
2
3
) δ
.09 (d, J ) 533 Hz, 1H), 4.93 (bs, 1H), 3.79 (d, J ) 12 Hz,
H), 3.15-3.25 (m, 2H), 1.7-1.9 (m, 4H), 1.44 (s, 9H); 13C NMR
J O015876I