Orthosilicate-mediated esterification of monosubstituted phosphinic acids

Article abstract of DOI:10.1021/ol006434g

(matrix presented) Monosubstituted phosphinic acids are esterified with orthosilicates in excellent yields. Phosphinylidene-containing acids react selectively under these conditions, while disubstituted phosphinic acids and phosphonic acids remain unchanged. One-pot procedures are also described for the preparation of phosphinate esters from an alcohol. This novel method provides a convenient and general alternative to more commonly employed conditions such as diazomethane or carbodiimide.

Full text of DOI:10.1021/ol006434g

ORGANIC
LETTERS
2000
Vol. 2, No. 21
3341-3344
Orthosilicate-Mediated Esterification of
Monosubstituted Phosphinic Acids
Yves R. Dumond, Rhonda L. Baker, and Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian UniVersity,
Fort Worth, Texas 76129
j.montchamp@tcu.edu
Received August 8, 2000
ABSTRACT
Monosubstituted phosphinic acids are esterified with orthosilicates in excellent yields. Phosphinylidene-containing acids react selectively
under these conditions, while disubstituted phosphinic acids and phosphonic acids remain unchanged. One-pot procedures are also described
for the preparation of phosphinate esters from an alcohol. This novel method provides a convenient and general alternative to more commonly
employed conditions such as diazomethane or carbodiimide.
Existing methods for the esterification of phosphinic acids
commonly use diazomethane and related diazoalkanes,1
carbodiimide/ alcohol,2 RCOCl/alcohol,3 and to a lesser
extent other reagents.4 However, these methods are not
selective for phosphinylidene-containing compounds and are
often either inconvenient or limited in the range of esters
that can be obtained. A largely overlooked exception is the
esterification with an alcohol under continuous water re-
moval.5 Unfortunately, this reaction is still limited to the
preparation of esters derived from high-boiling alcohols.
Accordingly, the general and selective esterification of
monosubstituted phosphinic acids 1 in the presence of other
phosphorus acids such as 2 is still difficult to achieve
(Scheme 1).
(1) (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, 116, 6508. (d) Baillie, A. C.; Cornell, C. L.;
Wright, B. J.; Wright, K. Tetrahedron Lett. 1992, 33, 5133.
Scheme 1
(2) (a) Karanewsky, D. S.; Badia, M. C. Tetrahedron Lett. 1986, 27,
1751. (b) Sampson, N. A.; Bartlett, P. A. J. Org. Chem. 1988, 53, 4500.
(c) Karanewsky, D. S.; Badia, M. C.; Cushman, D. W.; DeForrest, J. M.;
Dejneka, T.; Loots, M. J.; Perri, M. G.; Petrillo Jr.; E. W.; Powell, J. R. J.
Med. Chem. 1988, 31, 204. (d) Baylis, E. K. Tetrahedron Lett. 1995, 36,
9385. (e) Chen, S.; Coward, J. K. J. Org. Chem. 1998, 63, 502.
(3) (a) Qiao, L.; Nan, F.; Kunkel, M.; Gallegos, A.; Powis, G.;
Kozikowski, A. P. J. Med. Chem. 1998, 41, 3303. (b) 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. (c)
Willems, H. A. M.; Veeneman, G. H.; Westerduin, P. Tetrahedron Lett.
1992, 33, 2075.
In connection with studies related to the synthesis of
biologically active phosphinate compounds, we developed
a method to convert monosubstituted phosphinic acids into
the corresponding esters. Esters 3 (Scheme 1) are important
synthetic intermediates and final targets.6 In addition, a
method for selectively esterifying monosubstituted acids 1
over disubstituted acids 2 is especially valuable since most
(4) P(OAlk)3: (a) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood,
J. M. J. Med. Chem. 1989, 32, 1652. (b) Elepina, L. T.; Balakhontseva, V.
N.; Nifant′ev, E. E. J. Gen. Chem. USSR 1973, 43, 1795. (AlkO)2SO2: (c)
Hatt, H. H. J. Chem. Soc. 1933, 776. PCl5: (d) Natchev, I. A. Liebigs Ann.
Chem. 1988, 861. PyBOP/i-Pr2NEt: (e) Chen, S.; Lin, C.-H.; Walsh, C.
T.; Coward, J. K. Bioorg. Med. Chem. Lett. 1997, 7, 505.
(5) (a) Nifant’ev, E. E.; Kil’disheva, V. R.; Nasonovskii, I. S. Zh. Prikl.
Khim. 1969, 42, 2590. (b) Cherbuliez, E.; Weber, G.; Rabinowitz, J. HelV.
Chim. Acta 1963, 46, 2464. (c) Dumond, Y. R.; Baker, R. L.; Montchamp,
J.-L. Unpublished results.
(6) Many examples can be found in refs 1-4.
10.1021/ol006434g CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/26/2000

reactions used for the preparation of 1 produce varying
amounts of 2 (R1 ) R2 ) R) as a contaminant which cannot
be easily removed. Therefore, selective esterification would
allow easy purification of such mixtures by simple extraction,
leaving in the aqueous phase the unreacted impurity 2. In
contrast with adamantanamine and other salts which are
commonly used to purify 1, the ester product 3 is also
immediately available for further functionalization.
We now report a novel, selective, and high-yielding
method, which employs orthosilicates to esterify phosphinic
acids 1 and addresses the limitations outlined above. In a
typical procedure (conditions A), a phosphinic acid (5 mmol)
in toluene (15 mL) is treated with an orthosilicate (2.5-5.0
mmol), and the reaction mixture is refluxed for 24 h under
N2. At that time, the yield is determined by 31P NMR. The
solution is then concentrated under reduced pressure and
purified.7 Results are presented in Table 1.
identical conditions. This selectivity was further established
by conducting a competition experiment in which an
equimolar mixture of phenyl phosphinic acid, phenyl phos-
phonic acid, diphenyl phosphinic acid, and (EtO)4Si was
refluxed in toluene. After 24 h, 31P NMR analysis of the
reaction mixture revealed the formation of ethyl phenyl
phosphinate (88%) as the only ester product. In 1956, Sumrell
and Ham reported the successful esterification of carboxylic
acids with 0.5 equiv of an alkyl orthosilicate, without a
solvent.9 As a result, we also tested the reactivity of
carboxylic acids under our conditions. Interestingly, when
benzoic acid and hydrocinnamic acid were treated with 1
equiv of (EtO)4Si under conditions A, the corresponding
esters were obtained in <2% and 16% yields, respectively.
These experiments indicate that monosubstituted phosphinic
acids are selectively esterified and that the presence of a
phosphinylidene group is required for efficient esterification
to occur.
The number of transferrable groups from (EtO)4Si was
studied next by examining the influence of the orthosilicate
stoichiometry on the yield of phenyl phosphinate ester (Table
1, entries 1-4). It was found that the first two substituents
on silicon can both be transferred to phosphorus within 24
h, while the third and fourth substituents require heating for
an extended period of time. In entry 1, the yield went from
48% after 24 h, to 67% after 48 h, to 72% after 72 h. Using
2 equiv (entry 4) instead of 1 (entry 3) did not provide any
improvement. An equimolar equivalent of (R′O)4Si and RP-
(O)(OH)H was therefore routinely employed, although 0.5
equiv of (R′O)4Si also proved satisfactory (Table 1, compare
entries 3 vs 2 and 6 vs 7).
Reactions were typically conducted with 0.33 M phos-
phinic acid in toluene; yet the influence of the concentration
was also briefly studied. Doubling the concentration from
0.33 M (Table 1, entry 3, R′ ) Et, 90%) to 0.66 M gave the
ester in 93% yield. When the reaction was conducted neat,
the yield was also 93%. Finally, the reaction in entry 3 was
scaled up to 100 mmol without any difficulty, to provide
ethyl phenyl phosphinate in 88% yield.
Once these reaction parameters were established, the
influence of the alkoxy residue in (R′O)4Si was investigated.
It was found that R′ ) Me, Bu, Allyl, Ph gave the
corresponding esters in 91-100% yields (Table 1, entries
5-9), while R′ ) Et gave a slightly lower yield. Orthosilicate
reactivity appears proportional to the boiling point of R′OH
released in the medium.10 Due to the easy accessibility of
its silicon atom, (MeO)4Si escapes this trend and is the most
reactive.
The scope of the esterification was then probed with a
few other monosubstituted phosphinic acids. For example,
(4-phenylbutyl) phosphinic acid,2c octyl phosphinic acid,2c
and (R-hydroxydecyl) phosphinic acid11 all reacted smoothly
with various orthosilicates (Table 1, entries 10-15). Once
Table 1. Esterification of Monosubstituted Phosphinic Acids
with Orthosilicates (Method A)a
31P NMR
yield, %
RP(O)(OR′)H
equiv of (unreacted isolated yield,
entry
R
R′ (R′O)4Si
acid, %)
%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph(CH2)4
Ph(CH2)4
Ph(CH2)4
Ph(CH2)4
Oct
Et
Et
Et
Et
Me
Bu
Bu
Allyl
Ph
Me
Et
0.25
0.5
1.0
2.0
1.0
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
48 (52)
82 (18)
90 (10)
82 (18)
100 (0)
93 (7)
94 (6)
97 (3)
100 (0)
94 (0)
84 (7)
100 (0)
91 (3)
96 (0)
97 (3)
98 (2)
83
85
93
94
81
70
98
80
Bu
Allyl
Me
Allyl
Ph
Oct
Oct
87
65
C9H19CHOH Bu
85 (0)
a All reactions were conducted in refluxing toluene for 24 h.
While orthosilicates are available cheaply, and employed
extensively in the sol-gel process,8 a literature survey
showed a paucity of applications in organic synthesis. Under
conditions A, diphenyl phosphinic acid (2, R1 ) R2 ) Ph)
and phenyl phosphonic acid (2, R1 ) Ph, R2 ) OH) did not
give any detectable quantity of the corresponding esters,
while phenyl phosphinic acid (1, R ) Ph) gave ethyl phenyl
phosphinate in 90% yield (Table 1, entry 3), under otherwise
(7) Purification typically involves radial or flash chromatography on silica
gel. However, in favorable cases, a simple partitioning of the crude product
between CH3CN and hexane is sufficient to provide almost pure phosphinate.
The hexane layer contains the nonpolar silicon-derived impurities, while
the polar phosphinate ester remains in the CH3CN layer.
(8) For example, see: Loy, D. A.; Shea, K. J. Chem. ReV. 1995, 95,
1431, and references cited.
(9) Sumrell, G.; Ham, G. E. J. Am. Chem. Soc. 1956, 78, 5573. To our
knowledge, these conditions have not been employed since.
(10) Indeed, 1H NMR analysis of the reaction mixture obtained from
entry 7 revealed the presence of 2 mmol of BuOH.
(11) Albouy, D.; Brun, A.; Munoz, A.; Etemad-Moghadam, G. J. Org.
Chem. 1998, 63, 7223.
3342
Org. Lett., Vol. 2, No. 21, 2000

again, isolated yields were good to excellent. The facile
preparation of methyl phosphinates with method A is
particularly noteworthy as an alternative to the use of
diazomethane.
raphy. All runs were usually clean, with the desired esters
being formed almost exclusively. On occasion, small amounts
of unreacted acid and/or phenyl ester could be detected.14
As expected, when a small amount of phenyl ester remained,
addition of more R′OH typically resulted in complete
consumption of that reactive intermediate with a proportional
increase in yield.
Butyl phenyl phosphinate was obtained in 86% yield, using
only 1 equiv of 1-butanol and 0.55 equiv of (PhO)4Si (Table
2, entry 1). Compared to method A, method B is only slightly
lower yielding but allows the formation of esters directly
from the corresponding alcohol. Since tetraphenoxysilane is
commercially available, or prepared very cheaply from
phenol and either (EtO)4Si or SiCl4,15 this one-pot procedure
provides an easy solution to selectively esterify monosub-
stituted phosphinic acids with various alcohols.
Also in order to circumvent the need for a purified
orthosilicate in method A, another approach to directly
employ an alcohol was briefly investigated (method C, Table
2, entries 5, 6) where the orthosilicate is formed in situ. Once
again we focused on a straightforward one-pot process in
order to simplify the experimental procedure. Accordingly,
a toluene solution of SiCl4 (2.5-5.0 mmol), pyridine, and
R′OH (in a 1/4.4/4 ratio) is refluxed for 1 h, then treated
with the acid (5 mmol), and refluxed for 24 h (method C).
Once again, even with only 0.5 equiv of the reagent, butyl
phenyl phosphinate was obtained in good yield (Table 2,
entry 5, 85%). Secondary esters were also formed without
complications (Table 2, entries 4 and 6). On the other hand,
tertiary esters could not be obtained in useful yields with
any of the methods employed.
Finally, the generality of the orthosilicate-promoted es-
terification was explored with other alkoxysilanes. Trialkoxy-
silanes (R′O)3SiR′′ were capable of esterifying monosubsti-
tuted phosphinic acids, although at least 2 equiv was
necessary to reach a useful yield in 24 h. On the other hand,
the reaction of dialkoxysilanes proved very sluggish, even
when a large excess was employed. For example, reacting
phenyl phosphinic acid with 5 equiv of diethoxydimethyl-
silane for 24 h afforded the corresponding ester in only 44%
yield, and byproducts were also formed.
Since method A is limited by the availability of the
orthosilicate reagents, we then devised a more general
process which would directly employ an alcohol, based on
the observation that the phenyl esters were formed in nearly
quantitative yields (Table 1, entries 9 and 16) but were
unstable and could not be isolated as pure compounds.12 This
reactivity suggested that the phenyl esters could serve as
activated esters for the esterification of alcohols, and in fact,
related transesterifications of phenyl phosphates, phenyl
phosphonates, and phenyl phosphite are well-known to
proceed, but usually under basic conditions.13
A one-step esterification with alcohols for which the
corresponding orthosilicate is not readily available could
indeed be developed (method B). The results are presented
in Table 2 (entries 1-4). In this reaction, the phenyl ester is
Table 2. One-Pot Esterification of R-P(O)(OH)H with
Alcohols
equiv of
yield, %a
(acid, %)
entry
1
R
R′
R′OH
SiX4
Ph
Ph
Bu
Bn
1.0
2.0
2.0
2.0
2.0
4.0
0.55 equiv of
Si(OPh)4
0.6 equiv of
Si(OPh)4
0.6 equiv of
Si(OPh)4
0.6 equiv of
Si(OPh)4
86 (7)
92 (0)
2
3
4
5
6
Ph(CH2)4 3-pentyl
100 (0)
100 (0)
85 (15)
73 (14)b
Oct
Ph
Ph
cinnamyl
Bu
0.5 of SiCl4
+
2.2 of Pyr
1.0 of SiCl4 +
4.4 of Pyr
i-Pr
a Determined by 31P NMR. b Isolated yield was 73%.
first formed using method A and then transesterified in situ
with an alcohol under neutral conditions. Typically, a
phosphinic acid (5 mmol) and tetraphenoxysilane (3 mmol)
are refluxed in toluene (15 mL) for 24 h, then an alcohol
(5-10 mmol) is added, and the mixture is refluxed for an
additional 2-4 h (method B). The crude product obtained
after evaporation of the solvent is purified by chromatog-
In terms of usefulness, trialkoxysilanes may still find some
applications, if for example the use of hazardous tetramethyl
orthosilicate must be avoided. While the yields were gener-
ally a little lower (ca. 60-80%) using these reagents, the
only phosphorus-containing compound other than the desired
ester was the unreacted acid starting material. This suggested
a protocol which both provides a replacement for tetramethyl
orthosilicate and simplifies product purification (Scheme 2).
(12) Some phenyl esters (R′ ) Ph) have been prepared previously in
low or unreported yields and purity: (a) see ref 6a (R ) Bu). (b) Foss, V.
L.; Kudinova, V. V.; Lutsenko, I. F. J. Gen. Chem. USSR 1979, 49, 489 (R
) t-Bu). (c) Johnson, M. K. Biochem. Pharmacol. 1988, 37, 4095 (R )
Ph). (d) Yamashita, M.; Long, P. T.; Shibata, M. Carbohydr. Res. 1980,
84, 35 (R ) Ph). These esters are particularly sensitive to hydrolysis and
decompose on silica gel.
Scheme 2
(13) (a) Kers, A.; Kers, I.; Stawinski, J.; Kraszewski, A. Synthesis 1995,
427. (b) Billington, D. C.; Baker, R.; Kulagowski, J. J.; Mawer, I. M. J.
Chem. Soc., Chem. Commun. 1987, 314. (c) Ogilvie, K. K.; Beaucage, S.
L. Tetrahedron Lett. 1976, 1255. (d) Ogilvie, K. K.; Beaucage, S. L. J.
Chem. Soc., Chem. Commun. 1976, 443. (e) Slotin, L. A. Synthesis 1977,
737. (f) van Boom, J. H.; Burgers, P. M. J.; van Deursen, P.; Reese, C. B.
J. Chem. Soc., Chem. Commun. 1974, 618. (g) Jones, G. H.; Moffatt, G. J.
Am. Chem. Soc. 1968, 90, 5337.
Org. Lett., Vol. 2, No. 21, 2000
3343

When 3-aminopropyl trimethoxysilane hydrochloride16 4 was
heated with phenyl phosphinic acid, a nearly quantitative
yield of ester was observed by 31P NMR.17 After aqueous
workup, the ester was obtained cleanly in 72% yield. The
esterification with trialkoxysilane derivatives also opens up
new opportunities, for example, in the development of
polymer-supported reagents. These promising leads will be
the subject of future developments.
In conclusion, we have developed several protocols for
the selective esterification of monosubstituted acids in one
pot. The methods based on orthosilicate reagents provide the
esters in good to excellent yields under mild conditions.
Compared to other existing methodology for the synthesis
of monosubstituted phosphinate esters, our reaction offers
several advantages. The process has a broad scope and is
experimentally straightforward, cheap, scalable, selective, and
high yielding. For the preparation of methyl esters, tetra-
methyl orthosilicate offers significant advantages over dia-
zomethane, and when the toxicity of (MeO)4Si is an issue,
alternate procedures relying on alkyl trimethoxysilanes have
also been developed. Further developments of this chemistry,
its application to the preparation of biologically active
organophosphorus compounds, and mechanistic studies will
be reported in due course.
(14) The esterification also proceeded satisfactorily when all the reagents
were mixed together from the start (i.e., the phenyl ester was not preformed
first), even though in this case these two compounds often remained in
small amounts at the end of the reaction.
(15) For example, see: (a) Ismail, R. M.; Koetzsch, H. J. J. Organomet.
Chem. 1967, 10, 421 and references cited. (b) Malatesta, L. Gazz. Chim.
Ital. 1948, 78, 750.
(16) Hydrochloride 3 was most conveniently prepared from the com-
mercially available amine by exchange with NH4Cl. See: Speier, J. L.;
Roth, C. A.; Ryan, J. W. J. Org. Chem. 1971, 36, 3120.
(17) The reason for the high yield obtained with 4 compared to, for
example, propyltrimethoxysilane is unclear.
Acknowledgment. This work was supported by grants
from the Robert A. Welch Foundation and the Texas
Christian University Research and Creative Activities Fund.
Supporting Information Available: Spectroscopic data
and representative proton and carbon spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL006434G
3344
Org. Lett., Vol. 2, No. 21, 2000