Allylic phosphinates via palladium-catalyzed allylation of H-phosphinic acids with allylic alcohols

Article abstract of DOI:10.1021/ol8000415

A novel catalytic allylation of H-phosphinic acids is described. Using Pd/xantphos (2 mol %), H-phosphinic acids react directly with allylic alcohols to produce P-allylated disubstituted phosphinic acids.

Full text of DOI:10.1021/ol8000415

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1123-1126
Allylic Phosphinates via
Palladium-Catalyzed Allylation of
H-Phosphinic Acids with Allylic
Alcohols
Lae1titia Coudray, Karla Bravo-Altamirano, and Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian UniVersity,
Fort Worth, Texas 76129
j.montchamp@tcu.edu
Received January 8, 2008
ABSTRACT
Abstract A novel catalytic allylation of H-phosphinic acids is described. Using Pd/xantphos (2 mol %), H-phosphinic acids react directly with
allylic alcohols to produce P-allylated disubstituted phosphinic acids.
H-Phosphinic acids are increasingly available building blocks
which have been used extensively in the synthesis of a variety
of functionalized organophosphorus compounds.1 The func-
tionalization of H-phosphinic acids by standard methods
(such as base-promoted alkylation,2 palladium-catalyzed
cross-coupling with aryl halides,3 and radical addition to
alkenes4) is relatively well-developed. However, there is a
lack of methods which are general, are atom-economical,
are catalytic, and take place under mild conditions. Possible
exceptions are the recent work by Tanaka, Han, and Zhao
on the reaction of phenyl-H-phosphinate esters with alkynes
using palladium, nickel, or copper catalysts, and Stockland
with Michael acceptors using microwave irradiation without
any catalyst.5 However, this reaction appears limited to
phenyl-containing phosphinates, which behave quite differ-
ently from other H-phosphinates. In fact, we previously
observed the reactivity of phenyl-H-phosphinate esters in
radical reactions and their propensity for formation of a
second P-C bond.6
(1) (a) Montchamp, J.-L. Specialty Chem. Mag. 2006, 26, 44. (b)
Montchamp, J.-L. J. Organomet. Chem. 2005, 690, 2388.
(2) Abrunhosa-Thomas, I.; Sellers, C. E.; Montchamp, J.-L. J. Org. Chem.
2007, 72, 2851, and references cited therein.
(3) (a) Xu, Y.; Zhang, J. Synthesis 1984, 778. (b) Xu, Y.; Li, Z.; Xia, J.;
Guo, H.; Huang, Y. Synthesis 1983, 377. (c) Xu, Y.; Li, Z. Synthesis 1986,
240. (d) Xu, Y.; Zhang, J. J. Chem. Soc.. Chem. Commun. 1986, 1606. (e)
Xu, Y.; Wej, H.; Zhang, J.; Huang, G. Tetrahedron Lett. 1989, 30, 949. (f)
Huang, C.; Tang, X.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2006, 71,
5020. (g) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.-Eur. J. 2006,
12, 3636. (h) Lei, H.; Stoakes, M. S.; Schwabacher, A. W. Synthesis 1992,
1255.
(4) (a) Hirai, T.; Han, L.-B. Org. Lett. 2007, 9, 53. (b) Piettre, S. R.
Tetrahedron Lett. 1996, 37, 2233. (c) Zeiss, H.-J. Tetrahedron Lett. 1992,
38, 8263. (d) Dingwall, J. G.; Tuck, B. J. Chem. Soc., Perkin Trans. 1
1986, 2081. (e) Pudovik, A. N.; Konovalova, I. V.; Guryleva, A. A. J. Gen.
Chem. USSR 1963, 33, 2850. (f) Finke, M.; Kleiner, H.-J. Liebigs Ann.
Chem. 1974, 741.
We recently reported the palladium-catalyzed dehydrative
allylation of hypophosphorous acid with allylic alcohols (eq
(5) (a) Nune, S. K.; Tanaka, M. Chem. Commun. 2007, 2858. (b) Han,
L.-B.; Zhao, C.-Q.; Onozawa, S.-y.; Goto, M.; Tanaka, M. J. Am. Chem.
Soc. 2002, 124, 3842. (c) Han, L.-B.; Zhang, C.; Yazawa, H.; Shimada, S.
J. Am. Chem. Soc. 2004, 126, 5080. (d) Niu, M.; Fu, H.; Jiang, Y.; Zhao,
Y. Chem. Commun. 2007, 272. (e) Stockland, R. A. Jr. Taylor, R. I.;
Thompson, L. E.; Patel, P. B. Org. Lett. 2005, 7, 851.
(6) Depre`le, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745.
10.1021/ol8000415 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/21/2008

1), which leads to allylic H-phosphinic acids (RPO2H2 1).7
In this reaction, further allylation of the products 1 is not
observed, as H3PO2 is much more reactive. Mechanistically
there is no reason why an analogous reaction could not also
generally take place with 1, since the required tautomeric
equilibrium between the P(V) phosphinic and the P(III)
phosphonous forms is still available. One expected competing
side-reaction is the oxidation of 1 into the corresponding
phosphonic acid8 at the higher temperature that might be
required. Thus, more strict anhydrous and anaerobic condi-
tions are necessary than in eq 1.
Table 1. Palladium-Catalyzed Allylation of
Phenyl-H-Phosphinic Acida
Herein, we report the development and preliminary scope
of this novel reaction. In the case of the allylation of
H3PO2, we found DMF to be the optimum solvent.7 Seeking
a solvent which might catalyze the tautomeric equilibrium,
we reasoned that a hydrogen-bonding alcoholic medium
might be superior, but a further requirement is to prevent
direct esterification of 1 with the solvent which would
compete with the allylic alcohol. This led to the identification
of a tertiary alcohol. Further temperature (and cost) consid-
erations narrowed the choice to tert-amyl alcohol. To test
this hypothesis, H3PO2 was initially tested in this reaction.
Gratifyingly, it was found that tert-amyl alcohol could be
employed, even as a cosolvent, and good yields of cinnamyl-
H-phosphinic acid were obtained. In fact, when H3PO2 (1
equiv) was reacted with cinnamyl alcohol (2 equiv), in the
presence of 2 mol % Pd/xantphos (xantphos ) 9,9-dimethyl-
4,5-bis(diphenylphosphino)xanthene), in anhydrous tert-
amyl alcohol (3 Å MS, reflux, N2), the disubstituted
phosphinic acid 2 was obtained in quantitative isolated yield
(eq 2). In the absence of sieves, the yield is significantly
decreased (76%).
a See Supporting Information for experimental details. Freshly distilled
tert-AmOH was used (PhPO2H2 0.3-0.5 M). Entries 2-4 and 6-7:
powdered 3 Å sieves (1 g/mmol) added. b 31P NMR yields were determined
on the crude mixture of phosphinic acids. c Isolated yield. Benzyl esters
were purified by chromatography on silica gel, and the numbers represent
the overall yield of the allylation-esterification sequence. d Conducted with
0.25 mol % Pd/xantphos. e Reaction conducted in a sealed pressure tube
with 2 equiv of allylic alcohol.
must be added to obtain good yields and minimize formation
of PhPO3H2.8 Although the yields are moderate to good, the
catalytic allylation clearly takes place with a variety of allylic
alcohols. Of course, the reaction does not take place in the
absence of the palladium catalyst. The role of catalyst loading
was briefly investigated (entry 1), and as little as 0.25 mol
% Pd still resulted in a quantitative isolated yield (entry 1b).
With these results in hand, we set out to explore the scope
of the reaction using various H-phosphinic acid starting
materials since this could constitute a general route to useful
allylic derivatives. A range of H-phosphinic acids9 bearing
several functional groups reacted uneventfully with an
equimolar amount of cinnamyl alcohol (Table 2). As in Table
1, the majority of the disubstituted phosphinic acids was
isolated after esterification and chromatographic purification.
In the case of entry 6, using 2 equiv of cinnamyl alcohol
did not increase the yield.
This result provided the basis for the study of the allylation
of phenyl-H-phosphinic acids with various allylic alcohols
(Table 1). In most cases, the products were isolated after
in-situ esterification of the phosphinic acid. As expected,
when the reaction is not nearly quantitative, a significant
amount of the phosphonic acid (resulting from the oxidation
of the H-phosphinic acid starting material)8 constitutes the
balance of the product. This impurity is also esterified to
the phosphonate dibenzyl ester, which is separated during
the purification process, but typically lowers the overall
isolated yield of pure disubstituted phosphinic benzyl ester.
Unlike the reaction with H3PO2, which proceeds with high
E-selectivity,7 the present reaction is poorly selective (entries
4 and 7), possibly because of the more forcing reaction
conditions. In most cases, powdered 3 Å molecular sieves
A possible mechanism for the allylation of H-phosphinic
acids is shown in Scheme 1.10 Fischer-like esterification of
(9) See Supporting Information for details. The starting H-phosphinic
acids are available through methods we have developed. (a) Montchamp,
J.-L.; Dumond, Y. R. J. Am. Chem. Soc. 2001, 123, 510. (b) Depre`le, S.;
Montchamp, J.-L. J. Am. Chem. Soc. 2002, 124, 9386. (c) Depre`le, S.;
Montchamp, J.-L. Org. Lett. 2004, 6, 3805. (d) See also refs 1, 6, 7.
(7) Bravo-Altamirano, K.; Montchamp, J.-L. Org. Lett. 2006, 8, 4169.
(8) Bravo-Altamirano, K.; Montchamp, J.-L. Tetrahedron Lett. 2007, 48,
5755.
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Org. Lett., Vol. 10, No. 6, 2008

Scheme 1. Postulated Reaction Mechanism
Table 2. Allylation of H-Phosphinic Acids with Cinnamyl
Alcohola
π-allylpalladium intermediate, which collapses to intermedi-
ate 8 via 7, followed by reductive elimination to phosphinic
acid 9. An alternative pathway involves ion-pair 6, and the
attack of the P(III) phosphinate anion on the carbon atom of
the π-allylpalladium cation (path a) to produce directly
product 9. Attack at Pd in 612 produces 7, path b. Distin-
guishing between the two paths is rather difficult, and both
might be operative. However, the overall mechanism requires
a tautomeric equilibrium between P(V) and P(III) forms, and
therefore a phosphinylidene-containing unit [P(dO)H]. Pre-
liminary mechanistic experiments with preformed 4 indicate
that a species similar to 5 P(III) is likely involved since
catalyzed isomerization of silylated 4 (BSA as an additive)
is taking place rather efficiently.13 Similarly, various acidic
or basic additives also promote the rearrangement of
preformed 4.13 The use of tert-AmOH as a solvent likely
promotes the tautomeric equilibrium, and the addition of a
drying agent removes the water in the esterification process
and reduces the competing oxidation of 1.
Next, the synthetic utility of the reaction was briefly
investigated. Allylation is particularly useful because it
provides a handle for further synthetic elaboration. For
example, bis(cinammyl)phosphinic acid 2 (eq 2) was con-
verted into the rare [1,4]azaphosphinane-4-oxide ring sys-
tem14 through esterification, ozonolysis, and reductive am-
ination (Scheme 2). A similar sequence leads to the formation
a See Supporting Information for experimental details. Freshly distilled
tert-AmOH with powdered 3 Å sieves (1 g/mmol of 1) added. b 31P NMR
yields were determined on the crude reaction mixture of phosphinic acids.
c Isolated yield. Benzyl esters were purified by chromatography on silica
gel, and the numbers represent the overall yield of the allylation-esterification
sequence. d Pht ) phthalimide. e Molecular sieves were not used.
(11) pKa H3PO2 1.3, Khan, T. A.; Tripoli, R.; Crawford, J. J.; Martin,
C. G.; Murphy, J. A. Org. Lett. 2003, 5, 2971 (values around 2.0 can also
be found in the literature). pKa AcOH 4.76.
(12) Trost, B. M. Chem. ReV. 1996, 96, 395.
(13) Unpublished results. Bravo-Altamirano, K. Ph.D. dissertation, Texas
Christian University, May 2007.
(14) (a) Reznik, V. S.; Levin, Y. A.; Akamsin, V. D.; Galyametdinova,
I. V.; Pyrkin, R. I. Russ. Chem. Bull. 2000, 49, 495. (b) Levin, Y. A.; Pyrkin,
R. I.; Galyametdinova, I. Patent, U.S.S.R. 1974, SU 414264. (c) Manthey,
M. K.; Huang, D. T. C.; Bubb, W. A.; Christopherson, R. I. J. Med. Chem.
1998, 41, 4550.
1 with alcohol 3 provides allyl phosphinate 4. From there,
oxidative addition takes place via 5 (H-phosphinates are
better leaving groups than carboxylates)11 to provide a
(10) The mechanism is analogous to what we have proposed with H3PO2,
see ref 7 and Bravo-Altamirano, K.; Abrunhosa-Thomas, I.; Montchamp,
J.-L. J. Org. Chem. 2008, 73, 2292.
Org. Lett., Vol. 10, No. 6, 2008
1125

10, ring closing metathesis takes place smoothly but slowly
(∼71% conversion in 48 h). Nonetheless, phospholene 15
was obtained in acceptable yield.
Unfortunately, attempts at inducing the phospho-Cope
rearrangement17 of the product from Table 2, entry 4, both
under the literature conditions (NaOH, H2O, 195 °C) or using
microwave heating, were unsuccessful.
Scheme 2. Synthesis of the [1,4]Azaphosphinane-4-oxide
Heterocycle, Double Reductive Amination, and Ring-Closing
Metathesis of 3
In conclusion, we have developed the direct Pd-cata-
lyzed allylation of H-phosphinic acids with allylic alcohols.
Because of the flexibility provided by the allylic functional-
ity, the resulting disubstituted phosphinic acids are poten-
tially important intermediates in the synthesis of more
functionalized compounds. Applications to the synthesis of
phosphinopeptides and other biologically active compounds
are currently being pursued. Coupled with our previously
reported methods for the catalytic synthesis of H-phosphinic
acids, this reaction provides a general and environmentally
benign entry into symmetrically and differentially substituted
allylic phosphinic acids.
Acknowledgment. We thank the National Institute of
General Medical Sciences/NIH (1R01 GM067610) for the
financial 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.
of diamine 13 via double reductive-amination. Hydrogenoly-
sis produces bis(2-aminoethyl)phosphinic acid 14.15
Another application of intermediate 10 is the ring closing
metathesis to phospholene 15 (Scheme 2). Although the
formation of phospholenes via RCM is well-precedented,16
the precursors are always terminal alkenes. In the case of
OL8000415
(16) (a) Bujard, M.; Gouverneur, V.; Mioskowski, C. J. Org. Chem. 1999,
64, 2219. (b) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.;
Mioskowsky, C. Org. Lett. 2000, 2, 1517.
(15) Maier, L. Phosphorus, Sulfur Silicon Relat. Elem. 1992, 66, 67.
(17) Loewus, D. I. J. Am. Chem. Soc. 1981, 103, 2292.
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