Palladium-catalyzed cross-coupling of H-phosphinate esters with chloroarenes

Article abstract of DOI:10.1021/ol201222n

The palladium-catalyzed cross-coupling reaction between H-phosphinate esters and chloroarenes or chloroheteroarenes is described. This reaction is the first general metal-catalyzed phosphorus-carbon bond-forming reaction between a phosphorus nucleophile and chloroarenes.

Full text of DOI:10.1021/ol201222n

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3270–3273
Palladium-Catalyzed Cross-Coupling of
H-Phosphinate Esters with Chloroarenes
Eric L. Deal, Christelle Petit, and Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, Texas
76129, United States
j.montchamp@tcu.edu
Received May 8, 2011
ABSTRACT
The palladium-catalyzed cross-coupling reaction between H-phosphinate esters and chloroarenes or chloroheteroarenes is described. This
reaction is the first general metal-catalyzed phosphorusꢀcarbon bond-forming reaction between a phosphorus nucleophile and chloroarenes.
Disubstituted phosphinic acid esters are of paramount
importancein a variety of fields, especially asintermediates
for the synthesis of phosphine ligands, and in the prepara-
tion of biologically active compounds.1 A variety of metal-
catalyzed cross-coupling reactions have been developed
for the formation of PꢀC bonds.2 However, only a few of
these have been applied to chloroarene partners, and none
have been reported for unactivated cases.3
In terms of H-phosphinate esters specifically, only iso-
lated examples of cross-coupling with aryl halides have
been documented, most often with phenyl-H-phosphi-
nates, and/or using high palladium catalyst loadings
(5ꢀ10 mol %), typically delivering moderate yields.4 As
a part of our laboratory’s efforts at developing new
methodologies for the formation of PꢀC bonds, we
decided to tackle this problem and are now reporting the
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r
10.1021/ol201222n
Published on Web 05/25/2011
2011 American Chemical Society

first general cross-coupling of H-phosphinate esters with
aryl halides in general and chloroarenes in particular.
A possible mechanism for H-phosphinate coupling is
shownin Scheme 1. Key tothereaction isthe availability of
the P(III) nucleophile through tautomerization of the P(V)
phosphinylidene. While strong bases (like alkoxides) can
form the readily oxidized P(III) anion, this is not a likely
intermediate with the weak bases typically employed in
these reactions, and the advantage of increasing the con-
centration of a P(III) form can be offset by this anion’s
sensitivity to oxidation.
Table 1. Reaction Parameters with Bromobenzenea
cosolvent
31P NMR
yield (%)b
entry
solvent
additive
ligand
dppf
1
EG
none
none
EG
59
0
2
CH3CN
CH3CN
EtOH
dppf
3
dppf
63 (16)
30
4
none
EG
dppf
Scheme 1. Postulated Mechanism
5
EtOH
dppf
69 (7)
30
6
t-AmOH
t-AmOH
none
EG
dppf
7
dppf
72 (7)
5
8a
8b
9
dppf
DMF
none
xantphos
dppf
40
DMF
EG
71 (1)
7
10
11a
11b
11c
12
13
14a
14b
toluene
none
dppf
none
70 (5)
80 (7)c
90 (1)c
72 (5)
78 (7)
84 (4)
74 (17)g
dppf
toluene
EG
xantphos
dppf
toluene
toluene
PGd
DMEe
dppf
polymer
nixantphosf
toluene
EG
a Conditions: the reactions were conducted at reflux using solvent or
solvent/additive (9:1 v/v), or at 110 °C with DMF or neat EG. b Deter-
mined after addition of EtOH to obtain a homogeneous mixture. In a
few cases, some 2-hydroxyethyl ester also formed and the yield is
indicated in parentheses. c Run with 1 mol % Pd/ligand. d PG =
propylene glycol. e DME = 1,2-dimethoxyethane. f Polystyrene-sup-
ported Pd-nixantphos, 2 mol %. g Using catalyst from entry 14a.
During an investigation of the hydrophosphinylation of
H-phosphinates, we discovered the usefulness of ethylene
glycol (EG) as an additive to promote the tautomerization
of P(V) H-phosphinates into the reactive P(III) form.5 We
therefore attempted cross-coupling reactions using EG as
an additive anticipating it could also play a beneficial role.
The results of this investigation are reported below.
Ethyl octyl-H-phosphinate was chosen as a representa-
tive model compound (unlike aryl-H-phosphinate esters
which are special benzylic-like and activated, more easily
tautomerized substrates since electron-withdrawing groups
stabilize the P(III) form).6 Bromobenzene was also selected
as a more stringent test than reactive iodobenzene. Various
reaction parameters, such as solvents, bases, and ligands,
were explored.7 Table 1 summarizes some of these results
using 2 mol % Pd. Three ligands gave good results:
dppf, xantphos, and polymer-supported nixantphos.8 The
xantphos-like ligands are superior, whereas other ligands
tested were significantly poorer. Of the bases tried,
i-Pr2NEt and Et3N gave the best yields, but the former
was ultimately selected in order to reduce the potential for
dealkylation of the H-phosphinate starting material. Ethy-
lene glycol consistently gave remarkable improvements in
yields when added to other solvents. For example, with
EtOH the yield more than doubled (entry 5 versus 4).
It was found that the toluene/EG mixture gave the best
results even with only 1 mol % of catalyst (entries 11b and
11c). With toluene/EG (unlike other solvent mixtures) the
medium is heterogeneous, and the temperature is also
higher than that for entries 2ꢀ7.
At this time, we can only speculate about EG’s mode of
action in this reaction. The fact that little transesterification
to the 2-hydroxyethyl ester is observed rules out the
intramolecular PꢀH activation process we proposed for
hydrophosphinylation.5 We surmise that intermolecular
hydrogen bonding might still help in the tautomerization
of the P(V) H-phosphinate P(O)H into the active phos-
phonous P(III) form PꢀOH (Scheme 1), but this will need
to be investigated in future work. Ethylene glycol (entry 1)
is clearly superior to even other protic solvents, such as
EtOH and t-AmOH (entries 4 and 6). Another role for EG
ꢀ
(5) Petit, C.; Fecourt, F.; Montchamp, J.-L., submitted to Adv.
Synth. Catal.
(6) Coudray, L.; Montchamp, J.-L. Eur. J. Org. Chem. 2008, 3601.
(7) Some ligands tested include PPh3, dppe, dppp, 2-(di-tert-
butylphosphino)biphenyl, as well as the catalysts chloro(di-2-norbor-
nylphosphino)(20-dimethylamino-1,10-biphenyl-2-yl) palladium(II).
Bases tested include Na2CO3, K2CO3, Cs2CO3, K3PO4, DBU, DABCO,
and 1,1,3,3-tetramethylguanidine.
ꢁ
(8) Deprele, S.; Montchamp, J.-L. Org. Lett. 2004, 6, 3805.
Org. Lett., Vol. 13, No. 12, 2011
3271

might be to stabilize the palladium catalyst and slow down
its decomposition. For example, entry 11a still gave a
significant yield of product, even though it is conducted
in the absence of ligand. This might also explain why our
reaction can employ significantly less catalyst than in the
previously reported H-phosphinate Pd-catalyzed cross-
couplings.4 Interestingly, nontoxic propylene glycol (PG)
and DME are also good additives for this reaction (entries
12 and 13) even if EG is slightly superior. Another im-
portant result is the success of our readily available poly-
styrene Pd/nixantphos catalyst which delivered a yield
comparable to that of Pd/xantphos (entry 14a). Perhaps
more importantly, this catalyst could be used in a second
run without loss in PꢀC bond formation (91% total, entry
14b), althoughmore 2-hydroxylethyl ester formed, which is
a hallmark of a slower reaction (see also entries 3, 5, and 7).
With the promising results described above, we then
turned our attention to a study of the scope of the cross-
coupling between aryl halides and several H-phosphinate
esters. Using the conditions identified in Table 1 (2 mol %
Pd/xantphos, 1.3 equiv of i-Pr2NEt, toluene/EG (9:1, v/v),
110 °C), various combinations of RP(O)(OEt)H and ArX/
HetX were tried. These results are shown in Table 2.
Unsurprisingly, iodobenzene gave the cross-coupling
product in high yield (entry 1), as did phenyl triflate
(entry 2). More challenging bromobenzene also gave an
excellent result (entry 3), as expected from Table 1. Most
notably, even unactivated chlorobenzene still reacted to
deliver the disubstituted phosphinate in anacceptable yield
(entry 4a). The use of 1.5 equiv instead of the usual
equimolar ratio gave a clearly better outcome (entry 4b).
A reaction under microwave irradiation gave essentially
the same yield as the thermal reaction (entry 5b versus 5a).
Chloro(hetero)arenes cross-coupled with several repre-
sentative H-phosphinates. The more activated electron-
deficient aromatics gave higher yields, but a variety of aryl
and heteroaryl chlorides still reacted in moderate to good
yields (Table 2). For example, heterocyclic phosphinates
were obtained easily (entries 10ꢀ12). While H-phosphi-
nate esters are clearly weaker reducing agents than hypo-
phosphites, the formation of cross-coupled disubstituted
phosphinates remains a major breakthrough. This appears
to be the first general PꢀC bond formation via metal-
catalyzed cross-coupling employing chlorides.3
Table 2. Preliminary Scope of the Pd-Catalyzed Cross-Cou-
pling of Ethyl H-Phosphinate Esters with Aryl Halidesa
Unfortunately, deactivated chloroanisole (1.5 equiv)
only gave a low yield of cross-coupling with ethyl octyl-
H-phosphinate (29% NMR yield). Nonetheless, the pre-
sent work provides a very general entry into disubstituted
phosphinates. More reactive aryl halides (X = I, Br, OTf)
give high yields of cross-coupling, and these studies will be
included in the full account. While H-phosphinate esters
are much less reducing than the hypophosphorous deriva-
tives, their cross-coupling reactions have nonetheless been
more challenging than with H-phosphonates or secondary
phosphine oxides. Our reaction thus solves a long-standing
problem.
a See Supporting Information for experimental details. Unless
otherwise noted, equimolar amounts of H-phosphinate and aryl halide
were employed. b Determined after addition of EtOH to obtain a
homogeneous mixture. c Isolated after chromatography over silica
gel. d 1.5 equiv. e Conducted with microwave heating: constant tem-
perature mode at 130 °C.
Because xantphos, polystyrene-supported nixantphos,
and dppf were the best ligands we tested in this reaction,
and because they are also the preferred choice for a variety
of reactions we have developed (such as hydrophosphiny-
lation or coupling with hypophosphorous derivatives),6,9
3272
Org. Lett., Vol. 13, No. 12, 2011

this opens up the way for the investigation of various
tandem processes. Such sequences are important because
they would allow the synthesis of a variety of organopho-
sphorus compounds starting from hypophosphorous acid
and its derivatives, instead of the traditional but environ-
mentally problematic phosphorus trichloride (PCl3) and
related PꢀCl intermediates.10
was developed. Future work will aim at delineating the
exact role of ethylene glycol (and other additives), as well
as applications to the synthesis of important organopho-
sphorus compounds. Whatever the detailed molecular
mechanism for the additive, the present reaction provides
a highly general access to disubstituted phosphinates and
constitutes an exceptional example of catalytic PꢀC bond
formation with chloro(hetero)arenes. Further detailed in-
vestigations and applications will be disclosed in due course.
In conclusion, a novel and general palladium-catalyzed
cross-coupling between H-phosphinates and aryl halides
ꢁ
(9) (a) Deprele, S.; Montchamp, J.-L. J. Am. Chem. Soc. 2002, 124,
Acknowledgment. We gratefully acknowledge the Na-
tional Science Foundation (CHE-0953368) for financial
support.
9386. (b) Bravo-Altamirano, K.; Abrunhosa-Thomas, I.; Montchamp,
J.-L. J. Org. Chem. 2008, 73, 2292. (c) Coudray, L.; Montchamp, J.-L.
Eur. J. Org. Chem. 2008, 4101. (d) Belabassi, Y.; Bravo-Altamirano, K.;
Montchamp, J.-L. J. Organomet. Chem. 2011, 696, 106.
(10) For example, see: (a) Cossairt, B. M.; Piro, N. A.; Cummins,
C. C. Chem. Rev. 2010, 110, 4164. (b) Caporali, M.; Gonsalvi, L.; Rossin,
A.; Peruzzini, M. Chem. Rev. 2010, 110, 4178. (c) Scheer, M.; Balazs, G.;
Seitz, A. Chem. Rev. 2010, 110, 4236. (d) Trofimov, B. A.; Gusarova,
N. K. Mendeleev Commun. 2009, 19, 295. (e) Milyukov, V. A.; Budnikova,
Y. H.; Sinyashin, O. G. Russ. Chem. Rev. 2005, 74, 781. (f) Peruzzini, M.; de
los Rios, I.; Romerosa, A.; Vizza, F. Eur. J. Inorg. Chem. 2001, 593.
Supporting Information Available. Detailed experimen-
tal procedures, spectral data, and copies of the NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
Org. Lett., Vol. 13, No. 12, 2011
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