Single-step synthesis of secondary phosphine oxides

Article abstract of DOI:10.1021/om100571w

We report that in the presence of trifluoroacetic acid primary phosphines undergo efficient addition to aldehydes to form the corresponding secondary phosphine oxides in 47-97% yield. This transformation is compatible with aryl and alkyl phosphines, as well as a broad range of aldehydes, including formaldehyde. By using 1,5-dialdehydes as reaction partners, the addition provides a straightforward route to bis(phosphine oxides), which are difficult to prepare by alternative methods. In the presence of boron trifluoride diethyl etherate as reagent, benzophenone was shown to couple to phenylphosphine and cyclohexylphosphine in 92% and 72% yield, respectively. Twenty-three examples are presented.

Full text of DOI:10.1021/om100571w

Organometallics 2010, 29, 4193–4195 4193
DOI: 10.1021/om100571w
Single-Step Synthesis of Secondary Phosphine Oxides
Aaron J. Bloomfield, Jack M. Qian, and Seth B. Herzon*
Department of Chemistry, Yale University, New Haven, Connecticut 06520
Received June 9, 2010
Summary: We report that in the presence of trifluoroacetic
other phosphorus-containing reagents. For example, they
are easily elaborated to tertiary phosphine oxides,10 and both
secondary and tertiary phosphine oxides can be reduced in
high yields to form the cooresponding phosphines.11,12
acid primary phosphines undergo efficient addition to alde-
hydes to form the corresponding secondary phosphine oxides in
47-97% yield. This transformation is compatible with aryl
and alkyl phosphines, as well as a broad range of aldehydes,
including formaldehyde. By using 1,5-dialdehydes as reaction
partners, the addition provides a straightforward route to
bis(phosphine oxides), which are difficult to prepare by alter-
native methods. In the presence of boron trifluoride diethyl
etherate as reagent, benzophenone was shown to couple to
phenylphosphine and cyclohexylphosphine in 92% and 72%
yield, respectively. Twenty-three examples are presented.
In the course of our research we required access to complex
secondary phosphine oxides. Established methods for their
synthesis, such as alkylation of primary phosphine-borane
complexes,13 followed by deprotection and oxidation, or the
addition of organometal reagents to dialkyl phosphonates,14
did not provide the generality we required. In 1962, Epstein
and Buckler reported that heating of primary phosphines
and aldehydes or ketones in mineral acids formed R-hydroxy
tertiary phosphine oxides (4; eq 2).15-17 These reactions were
suggested to proceed via the secondary phosphine oxide, but
in only two instances could the reaction be stopped at this
stage. Namely, the addition of cyclohexylphosphine to cy-
clohexanone in refluxing concentrated hydrochloric acid
formed dicyclohexylphosphine oxide in 52% yield. Under
Secondary phosphine oxides are an important class of
reagents that find many applications in synthesis and
catalysis.1 Secondary phosphine oxides exist as a tautomeric
mixture of P(V) (1) and P(III) (2) isomers, with the air-stable
P(V) tautomer 1 predominating under ambient conditions
(eq 1).2 In the presence of a metal this equilibrium is driven
toward the P(III) tautomer via coordination.3 The phosphi-
nous acid complexes so formed (3) are active catalysts for
cross-coupling,4 hydrogenation,5 allylic alkylation,6 and
C-H arylation reactions.7,8 Racemic secondary phosphine
oxides are readily resolved using derivatives of tartaric acid.9
Secondary phosphine oxides may also serve as precursors to
(10) (a) Haynes, R. K.; Au-Yeung, T.-L.; Chan, W.-K.; Lam, W.-L.;
Li, Z.-Y.; Yeung, L.-L.; Chan, A. S. C.; Li, P.; Koen, M.; Mitchell, C. R.;
Vonwiller, S. C. Eur. J. Org. Chem. 2000, 3205. (b) Trofimov, B. A.;
Sukhov, B. G.; Malysheva, S. F.; Belogorlova, N. A.; Arbuzova, S. N.; Tunik,
S. P.; Gusarova, N. K. Russ. J. Org. Chem. 2004, 40, 129. (c) Hirai, T.; Han,
L.-B. Org. Lett. 2007, 9, 53.
(11) Selected methods for the reduction of secondary phosphine
oxides: (a) Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.;
Hrapchak, M.; Latli, B.; Lee, H.; Sabila, P.; Saha, A.; Sarvestani, M.;
Shen, S.; Varsolona, R.; Wei, X.; Senanayake, C. H. Org. Lett. 2005, 7,
4277. (b) Berthod, M.; Favre-Reguillon, A.; Mohamad, J.; Mignani, G.;
Docherty, G.; Lemaire, M. Synlett 2007, 1545.
*To whom correspondence should be addressed. E-mail: seth.
herzon@yale.edu.
(1) Berlin, K. D.; Butler, G. B. Chem. Rev. 1960, 60, 243.
(2) For studies and discussions of the factors effecting this equilibri-
um, see: (a) Brass, H. J.; DiPrete, R. A.; Edwards, J. O.; Lawler, R. G.;
Curci, R.; Modena, G. Tetrahedron 1970, 26, 4555. (b) Hoge, B.;
€
Neufeind, S.; Hettel, S.; Wiebe, W.; Thosen, C. J. Organomet. Chem.
2005, 690, 2382. (c) Hoge, B.; Garcia, P.; Willner, H.; Oberhammer, H.
Chem. -Eur. J. 2006, 12, 3567.
(3) Walther, B. Coord. Chem. Rev. 1984, 60, 67.
(4) (a) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66,
8677. (b) Li, G. Y. J. Organomet. Chem. 2002, 653, 63. (c) Li, G. Y. J. Org.
Chem. 2002, 67, 3643. (d) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D.
Angew. Chem., Int. Ed. 2005, 44, 7216. (e) Xu, H.; Ekoue-Kovi, K.; Wolf, C.
J. Org. Chem. 2008, 73, 7638. (f) Yang, D. X.; Colletti, S. L.; Wu, K.; Song,
M.; Li, G. Y.; Shen, H. C. Org. Lett. 2009, 11, 381. (g) Ackermann, L.;
Kapdi, A. R.; Schulzke, C. Org. Lett. 2010, 12, 2298.
(5) (a) Guillen, F.; Rivard, M.; Toffano, M.; Legros,
J.-Y.; Daran, J.-C.; Fiaud, J.-C. Tetrahedron 2002, 58, 5895. (b) Jiang,
X.-b.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.; Duchateau, A. L. L.;
Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G. Org. Lett. 2003, 5, 1503.
(c) Jiang, X.-b.; van den Berg, M.; Minnaard, A. J.; Feringa, B. L.; de Vries,
J. G. Tetrahedron: Asymmetry 2004, 15, 2223.
(6) Dai, W.-M.; Yeung, K. K. Y.; Leung, W. H.; Haynes, R. K.
Tetrahedron: Asymmetry 2003, 14, 2821.
(7) (a) Ackermann, L. Org. Lett. 2005, 7, 3123. (b) Ackermann, L.;
Vicente, R.; Hofmann, N. Org. Lett. 2009, 11, 4274.
(8) For selected reviews, see: (a) Dubrovina, N. V.; Boerner, A. Angew.
Chem., Int. Ed. 2004, 43, 5883. (b) Ackermann, L. Synthesis 2006, 1557.
(c) Ackermann, L. Phosphorus Ligands Asymmetric Catal. 2008, 2, 831.
(9) Holt, J.; Maj, A. M.; Schudde, E. P.; Pietrusiewicz, K. M.; Sieron,
L.; Wieczorek, W.; Jerphagnon, T.; Arends, I. W. C. E.; Hanefeld, U.;
Minnaard, A. J. Synthesis 2009, 2061.
(12) Selected methods for the reduction of tertiary phosphine oxides:
(a) Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem. Soc. 1969, 91, 7012.
(b) Marsi, K. L. J. Org. Chem. 1974, 39, 265. (c) Coumbe, T.; Lawrence,
N. J.; Muhammad, F. Tetrahedron Lett. 1994, 35, 625. (d) Imamoto, T.;
Kikuchi, S.-i.; Miura, T.; Wada, Y. Org. Lett. 2000, 3, 87. (e) Busacca, C. A.;
Raju, R.; Grinberg, N.; Haddad, N.; James-Jones, P.; Lee, H.; Lorenz, J. C.;
Saha, A.; Senanayake, C. H. J. Org. Chem. 2008, 73, 1524. See also ref 11b.
(13) Brunel, J. M.; Faure, B.; Maffei, M. Coord. Chem. Rev. 1998,
178-180, 665.
(14) (a) Emmick, T. L.; Letsinger, R. L. J. Am. Chem. Soc. 1968, 90,
3459. (b) Hays, H. R. J. Org. Chem. 1968, 33, 3690. (c) Neumaier, H.
Preparation of Secondary Phosphine Oxides via Grignard Reaction of
Phosphinic Acid Esters. D.E. Patent 88-3824776, 1990. (d) Leyris, A.;
Bigeault, J.; Nuel, D.; Giordano, L.; Buono, G. Tetrahedron Lett. 2007,
48, 5247. (e) Xu, Q.; Zhao, C.-Q.; Han, L.-B. J. Am. Chem. Soc. 2008, 130,
12648.
(15) Epstein, M.; Buckler, S. A. Tetrahedron 1962, 18, 1231.
(16) For the addition of phosphine to aldehydes and ketones, see: (a)
Buckler, S. A. J. Am. Chem. Soc. 1960, 82, 4215. (b) Buckler, S. A.;
Epstein, M. J. Am. Chem. Soc. 1960, 82, 2076.
(17) For the Lewis acid-mediated addition of secondary phosphines
to aldehydes, see: Suzuki, K.; Hashimoto, T.; Maeta, H.; Matsumoto,
T. Synlett 1992, 125.
r
2010 American Chemical Society
Published on Web 08/31/2010
pubs.acs.org/Organometallics

4194 Organometallics, Vol. 29, No. 18, 2010
Bloomfield et al.
Table 1. Secondary Phosphine Oxides Formed by Addition of
Phenylphosphine to Aldehydes and Ketonesa
Table 2. Secondary Phosphine Oxides Formed by Addition of
Cyclohexyl- and tert-Butylphosphine to Aldehydes and Ketonesa
a All reactions were conducted in deoxygenated trifluoroacetic acid
employing distilled phenylphosphine (prepared by reduction of dichlor-
ophenylphosphine; see Supporting Information), unless otherwise
noted. b Isolated yield after purification by flash-column chromatogra-
phy, unless otherwise noted. c Reaction conducted using commercial
phenylphosphine, without prior distillation. d Reaction conducted with-
out prior deoxygenation of trifluoroacetic acid. e Isolated as a 1.5:1
mixture of diastereomers. f Product was obtained in >95% purity after
aqueous workup (see Supporting Information). g Isolated as a 1:1
mixture of diastereomers. h Reaction performed using BF3 OEt2 (1.79
3
equiv) in toluene (0.3 M) at 80 °C.
similar conditions, the addition of phenylphosphine to acet-
ophenone formed (R-methylbenzyl)phenylphosphine oxide
in 45% yield.
a All reactions were conducted in deoxygenated trifluoroacetic acid.
b Isolated yield after purification by flash-column chromatography,
unless otherwise noted. c Isolated as a 1:1 mixture of diastereomers.
d Product was obtained in >95% purity after aqueous workup (see
Supporting Information). e Isolated as a 1.1:1 mixture of diastereomers.
f Reaction performed using BF3 OEt2 (1.40 equiv) in toluene (0.3 M) at
3
80 °C.
We revisited this reaction with the goal of finding conditions
that would allow for isolation of the secondary phosphine
oxides. A number of Lewis and Brønsted acids were eval-
uated for their ability to couple alkyl and aryl phosphines
with different aldehydes and ketones. As described below, we
found that heating a mixture of the aldehyde and phosphine
in trifluoroacetic acid as solvent formed the corresponding
secondary phosphine oxides in 47-97% yield. When using
ketones as the coupling partner, boron trifluoride diethyl
etherate in toluene was determined to be superior.

Note
The scope of the aldehydes that underwent efficient reac-
Organometallics, Vol. 29, No. 18, 2010 4195
67% yield by addition of phenylphosphine to 1,3-diformyl-
2-iodo-5-methylbenzene. The bis(phosphine)oxide products
5g and 5h were isolated as mixtures of meso and d/l isomers
(dr = 1-1.5:1). Although difficult to purify by flash-column
chromatography, 5g and 5h could be obtained in >97%
purity by extraction of an aqueous solution of the unpurified
reaction mixture with nonpolar solvents to remove less polar
impurities, followed by dichloromethane extraction to iso-
late the bis(phosphine oxide) products. Finally, we found
that non-enolizable ketones such as benzophenone reacted in
high yield when boron trifluoroide diethyl etherate was used
to promote the reaction (92%, entry 11).
To investigate the influence of the phosphorus substituent
on this transformation, we evaluated the addition of cyclo-
hexyl- and tert-butylphosphine to the aldehydes shown in
Table 2. In general, we found that the addition of alkylpho-
sphines to aldehydes occurred with efficiencies similar to that
of phenylphosphine, affording the secondary phosphine
oxide products 6a-m in 47-97% yield. The addition of
cyclohexylphosphine to benzophenone in the presence of
boron trifluoride diethyl etherate also occurred smoothly to
provide the phosphine oxide product 6n in 72% yield (entry 14).
In summary, we have shown that in the presence of
trifluoroacetic acid or boron trifluoride diethyletherate
primary phosphines may be coupled with aldehydes and
ketones in moderate to excellent yield. This reaction is
operationally simple and allows direct access to a variety
of secondary phosphine oxides, including products that
may serve as CP and PCP ligands. The synthesis of novel
organometallic complexes incorporating these ligands is
currently under investigation.
tion with phenylphosphine is shown in Table 1. Benzalde-
hyde reacted cleanly to afford benzylphenylphosphine oxide
(5a) in 89% yield (entry 1). Monitoring of this reaction by 31P
NMR revealed nearly complete conversion of phenylpho-
sphine within 20 min at 80 °C. However, we have observed a
wide distribution of reaction times between aldehyde sub-
strates, and to ensure quantitative conversion each reaction
was conducted with heating for 12-24 h. We note two
important points regarding the practicality of this reaction.
First, although the experiments depicted in Table 1 employed
phenylphosphine that was obtained by lithium aluminum
hydride reduction of dichlorophenylphosphine, followed by
distillation (see Supporting Information),18 comparable yields
were obtained with commercial, unpurified phenylphosphine
(88%, entry 2). In addition, although deoxygenation of the
trifluoroacetic acid solvent (freeze-pump-thaw) was neces-
sary to obtain the highest yields of product, the reaction still
proceeded smoothly without this measure (compare entries 1
and 3).
By analogy to the reactivity of benzaldehyde, ortho-iodo-
benzaldehye and ortho-bromobenzaldehyde also reacted in
good yield to form the corresponding halogenated phos-
phine oxide products 5b and 5c, respectively (entries 4 and 5).
These products (5b and 5c) are envisioned to be useful
precursors for the synthesis of transition metal complexes
incorporating bidentate C,P-ligands. Non-enolizable alde-
hydes such as pivaldehyde (entry 6) and mesityl aldehyde
(entry 7) formed the corresponding secondary phosphine
oxides 5d and 5e in 75% and 74% yield, respectively. The
successful addition to paraformaldehyde (71%, entry 8) is
important, as it provides direct access to differentially sub-
stituted P-methylated phosphine oxides, avoiding the gene-
ration of methylphosphine.19 In addition, two novel PCP
ligands were easily prepared by this method (entries 9, 10).
Heating of isophthalylaldehyde with phenylphosphine
formed the bis(phosphine oxide) 5g in 72% yield. Alterna-
tively, the iodinated PCP ligand precursor 5h was obtained in
Acknowledgment. We thank Professor Nilay Hazari
for a gift of cyclohexylphosphine. Acknowledgement is
made to the donors of the American Chemical Society
Petroleum Research Fund and to Yale University for
support of this research.
Supporting Information Available: Detailed experimental
procedures and spectral data (1H, 13C, and 31P NMR, IR, and
HRMS) for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) Arthur, F.; Gardner, P. J.; Gupta, K. K. S. J. Chem. Soc. 1966,
1162.
(19) Hirsekorn, K. F.; Veige, A. S.; Wolczanski, P. T. J. Am. Chem.
Soc. 2006, 128, 2192.