Green, palladium-catalyzed synthesis of benzylic H-phosphinates from hypophosphorous acid and benzylic alcohols

Article abstract of DOI:10.1002/ejoc.200800581

Benzylic alcohols cross-couple directly with concentrated H ₃PO₂ by using Pd/xantphos (1 or 2 mol-%). Depending on the substrate, DMF at 110 °C or t-AmOH at reflux with a Dean-Stark trap can be used. A broad range of benzylic alcohols react successfully to give moderate to good yields of the products. The preparation of other organophosphorus compounds (phosphinic and phosphonic acids) is also demonstrated. Asymmetric reaction with (R)-1-(2-naphthyl)-ethanol provids the corresponding H-phosphinic acid in 77% ee. The methodology provides a green, PCl₃-free route to benzylic-H-phosphinic acids. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800581

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800581
Green, Palladium-Catalyzed Synthesis of Benzylic H-Phosphinates from
Hypophosphorous Acid and Benzylic Alcohols
Laëtitia Coudray[a] and Jean-Luc Montchamp*[a]
Keywords: Phosphorus / Cross-coupling / Organophosphorous compounds / Alcohols / Palladium / Homogeneous catalysis
Benzylic alcohols cross-couple directly with concentrated
H3PO2 by using Pd/xantphos (1 or 2 mol-%). Depending on
the substrate, DMF at 110 °C or t-AmOH at reflux with a
Dean–Stark trap can be used. A broad range of benzylic
alcohols react successfully to give moderate to good yields
of the products. The preparation of other organophosphorus
compounds (phosphinic and phosphonic acids) is also
demonstrated. Asymmetric reaction with (R)-1-(2-naphthyl)-
ethanol provids the corresponding H-phosphinic acid in 77%
ee. The methodology provides a green, PCl3-free route to
benzylic-H-phosphinic acids.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
to achieve the “green”, catalytic synthesis of benzylic-H-
phosphinates without the need for any prior activation.
Preparation from H3PO2 is ideal in terms of atom-economy
(the by-product is water). On the basis of our previous work
on allylic alcohols,[8] we expected a similar reaction (Fisher
esterification, Pd-catalyzed ionization, rearrangement, and
ultimately P–C bond formation) to be reasonable for ben-
zylic alcohols. Indeed, this proved to be the case.[9]
Introduction
Phosphorus trichloride is the main building block in the
“organophosphorus economy”;[1] however, the chlorine
atoms are not typically retained in the final products. Phos-
phorus–carbon bond-forming reactions are the object of in-
tense studies because of the fact that organophosphorus
compounds have a major impact in everyday life, from
phosphane ligands in catalysis, to phosphonates and phos-
phinates as extractants, flame retardants, and biologically
active molecules.[2] Our research focuses on hypophosphor-
ous compounds and H-phosphinic acid derivatives as flexi-
ble intermediates in the preparation of a variety of phos-
phorus functionalities.[3] H-Phosphinic acids are nearly
ideal for this purpose because they can be derivatized to
most of the important phosphorus-containing functionali-
ties.[4]
(1)
Herein we describe the first cross-coupling of benzylic
alcohols without any prior activation (as ester, carbonate,
or halide derivative compounds, which are often less avail-
able than the parent alcohol) to prepare H-phosphinates.
There are a few examples of benzylic acetate couplings,[5]
which include in situ activation,[5a] but none that proceed
through the benzylic alcohol directly.[6] Recently, we de-
scribed the synthesis of allylic-H-phosphinates from H3PO2
and allylic acetates[7] or alcohols[8] [Equation (1)]. Realizing
that this type of reaction should constitute a general pattern
of reactivity, similar to that of benzylic acetates, we investi-
gated benzylic alcohols in place of allylic alcohols in order
Results and Discussion
Initially, we investigated the reaction of 1- and 2-naph-
thylmethanol on the basis of Fiaud’s success with the corre-
sponding acetates.[5b,5c] Using Pd/xantphos (1 mol-%) and
DMF at 110 °C, we obtained good yields for the cross-
coupling (82% and 93% isolated yields, respectively:
Table 1, Entries 1 and 2).
Table 1 shows that these conditions were also satisfactory
for other substrates (Table 1, Entries 3–8a). No P–C bond
formation was observed in the absence of catalyst. However,
some substrates reacted inefficiently or not at all. Our re-
cent discovery of tert-amyl alcohol (t-AmOH) as a reaction
solvent to promote the PV to PIII tautomeric equilibrium
necessary for P–H bond activation[8] provided another set
of conditions that often succeeded when DMF gave poor
results (Table 1, Entries 8b–16).
[a] Department of Chemistry, Texas Christian University,
Box 298860, Fort Worth, Texas 76129, USA
Fax: +1-817-257-5851
E-mail: j.montchamp@tcu.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2008, 4101–4103
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Coudray, J.-L. Montchamp
SHORT COMMUNICATION
Table 1. Scope of the palladium-catalyzed benzylation.[a]
zylation–oxidation reaction to produce phosphonic acids in
a catalytic and environmentally friendly manner (com-
pound 4).[13] The catalytic allylation of benzylic-H-phos-
phinic acids can also be achieved.[14]
Scheme 1. Tandem transformations through benzylation. Reagents
and conditions: (a) concentrated H3PO2 (0.5 equiv.), Pd2(dba)3
(dba = dibenzylideneacetone) (0.5 mol-%), xantphos (1.1 mol-%),
t-AmOH, Dean–Stark, reflux, N2, 16 h; (b) PhP(O)(OH)H
(1.0 equiv.), Pd2(dba)3 (0.5 mol-%), xantphos (1.1 mol-%), t-
AmOH, reflux, N2, 17 h; (c) concentrated H3PO2 (2.0 equiv.),
Pd2(dba)3 (0.5 mol-%), xantphos (1.1 mol-%), DMF 110 °C, N2,
15 h; then open to air, 110 °C, 8 h.
The possibility for an asymmetric variant of this ben-
zylation was then examined with the commercially available
chiral (R)-1-(2-naphthyl)ethanol (Ͼ97% ee). The corre-
sponding H-phosphinic acid was obtained in 77% ee [Equa-
tion (2)]. In this case, some competing racemic side reaction
is taking place, most likely by β-hydrogen elimination–hy-
drophosphinylation. A control reaction with 2-vinylnaph-
thalene [Equation (3)] reveals the formation of a mixture
of racemic (1-naphthalen-2-yl-ethyl)phosphinic acid and (1-
naphthalen-2-yl-ethyl)phosphinic acid (iso/linear 78:22),
which indicates that some asymmetric induction is still ob-
served when starting from the alcohol, perhaps via the un-
dissociated alkene (if the alkene dissociates, the enantio-
meric excess would be expected in the range 50–55%). This
approach does provide a significantly enantio-enriched H-
phosphinic acid (the enantiomeric excess is comparable to
or better than that of other asymmetric reactions with ben-
zylic electrophiles),[5b,5e] which can be a precursor to a vari-
ety of other organophosphorus compounds.
[a] In all cases, 1 mol-% Pd was used under N2. Entries 1–8a: DMF,
110 °C; Entries 8b–16: t-AmOH, reflux, Dean–Stark trap. [b] Iso-
lated after extractive workup (R = H), ammonium salt precipi-
tation (R = NH4), or esterification with (BuO)4Si (R = Bu).
As shown in Table 1, a broad range of substrates were
converted into the corresponding H-phosphinic acids di-
rectly. This reaction provides a valuable and straightforward
route to benzylic H-phosphinic acids and their derivatives.
Alternate synthetic methods are much less desirable.[10] In
Table 1, the acids were often isolated after a simple extrac-
tive workup or by precipitation as the ammonium salt.
With some hydrophilic H-phosphinic acids, esterification[11]
was necessary in order to isolate the pure products. With t-
AmOH as the solvent, some side reactions are also some-
times observed, through elimination followed by hydro-
phosphinylation.[12] In this case, esterification or precipi-
tation is necessary to obtain pure coupling products. Over-
all, the direct benzylation of H3PO2 is a novel and efficient
catalytic reaction, which alleviates the use of atom-wasteful
procedures.
(2)
(3)
Scheme 1 illustrates some catalytic transformations in
which this benzylation can be employed to prepare other
compounds: (a) the catalytic benzylation of an H-phos-
phinic acid (compounds 2 and 3), and (b) the one-pot ben-
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Eur. J. Org. Chem. 2008, 4101–4103

Green, Palladium-Catalyzed Synthesis of Benzylic H-Phosphinates
phosphorus Chemistry, Wiley, New York, 2000, pp. 408; h) P.
Savignac, B. Iorga in Modern Phosphonate Chemistry, CRC
Press, Boca Raton, 2003, pp. 556.
Conclusions
In conclusion, we have demonstrated the first cross-
coupling of benzylic alcohols and its application to the for-
mation of H-phosphinic acids and some derivatives. The
reaction appears to be quite general and should be useful
in the “green” preparation of organophosphorus building
blocks. Preliminary results on the asymmetric variant are
presented. Future work will be aimed at studying and im-
proving the asymmetric benzylation of H3PO2, as well as
investigating the mechanism and scope of the reaction in
more detail. The environmentally friendly, halogen-free
preparation of building blocks is an important objective,
which continues to be a major focus in our laboratory.
[3] a) J.-L. Montchamp, Specialty Chemicals Magazine 2006, 26,
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Experimental Section
General Procedure for the Catalytic Benzylation of H3PO2 with Ben-
zylic Alcohols: Pd2(dba)3 (0.5 mol-%, 0.01 mmol) and xantphos
(1.1 mol-%, 0.022 mmol) were added to
[6] B. Liégault, J.-L. Renaud, C. Bruneau, Chem. Soc. Rev. 2008,
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a benzylic alcohol
[7] K. Bravo-Altamirano, I. Abrunhosa-Thomas, J.-L. Mont-
champ, J. Org. Chem. 2008, 73, 2292–2301.
(1 equiv., 2.0 mmol) and concentrated H3PO2 (2 equiv., 4.0 mmol)
dissolved in t-AmOH (0.2 , 10.0 mL) or in DMF (0.2 , 10.0 mL)
at room temperature. The reaction mixture was heated at reflux
(Dean–Stark trap) under N2 for 13–15 h when t-AmOH was used
or heated at 110 °C under N2 for 17 h for DMF. After the reaction
mixture was cooled, the product was then isolated as the acid, the
ammonium salt, or the butyl ester (see details in Supporting Infor-
mation).
[8] K. Bravo-Altamirano, J.-L. Montchamp, Org. Lett. 2006, 8,
4169–4171.
[9] Mechanistic experiments with independently prepared benzylic
phosphinates, the presumed intermediates, showed that the re-
arrangement took place in good yields. Benzylic phosphates
have been shown to undergo oxidative addition: M. McLaugh-
lin, Org. Lett. 2005, 7, 4875–4878.
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Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures and detailed spectroscopic
data for all products, mechanistic experiments, and details for
Equation (2) are presented (106 pages).
Acknowledgments
We thank the National Institute of General Medical Sciences/NIH
(1R01 GM067610) for financial support of this research.
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Received: June 15, 2008
Published Online: July 11, 2008
Eur. J. Org. Chem. 2008, 4101–4103
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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