Pd(0)-catalyzed phosphorus-carbon bond formation. Mechanistic and synthetic studies on the role of the palladium sources and anionic additives

Article abstract of DOI:10.1021/om700797k

Pd(PPh₃)₄, Pd(dba)₂, Pd(OAc)₂, and PdCl₂, have been evaluated as possible Pd(0) sources for the palladium-catalyzed P-C bond formation via a cross-coupling of aryl halides with H-phosphonate diesters. It was found that the most efficient catalytic system can be generated from Pd(OAc)₂ with a key role being played by Pd(II) and Pd(0) species with coordinated acetate ions. The reactivity of differently ligated Pd(II) complexes was determined, and ³¹P NMR spectroscopy studies were carried out to provide mechanistic interpretations for the observed differences between the catalytic systems.

Full text of DOI:10.1021/om700797k

5840
Organometallics 2007, 26, 5840-5847
Pd(0)-Catalyzed Phosphorus-Carbon Bond Formation. Mechanistic
and Synthetic Studies on the Role of the Palladium Sources and
Anionic Additives
Marcin Kalek† and Jacek Stawinski*,†,‡
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity, S-106 91 Stockholm,
Sweden, and Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14,
61-704 Poznan, Poland
ReceiVed August 6, 2007
Pd(PPh3)4, Pd(dba)2, Pd(OAc)2, and PdCl2, have been evaluated as possible Pd(0) sources for the
palladium-catalyzed P-C bond formation via a cross-coupling of aryl halides with H-phosphonate diesters.
It was found that the most efficient catalytic system can be generated from Pd(OAc)2 with a key role
being played by Pd(II) and Pd(0) species with coordinated acetate ions. The reactivity of differently
ligated Pd(II) complexes was determined, and 31P NMR spectroscopy studies were carried out to provide
mechanistic interpretations for the observed differences between the catalytic systems.
The development in the field of organometallic chemistry has
been driven by two major areas of its applications: the synthesis
of substituted, especially chiral, phosphine ligands, and natural
product synthesis.14 Due to mildness of the reaction conditions,
Pd-catalyzed cross-couplings provide access to a large number
of compounds, with diverse structural features, that cannot be
obtained in other ways.15 In natural product synthesis, nucleic
acids and their analogues became attractive synthetic targets
for the transition-metal-catalyzed reactions, due to the growing
interest in modified oligonucleotides as potential antisense/
antigene agents.16 In recent years several reports from this17
and other18-20 laboratories appeared on the synthesis of
phosphorus-modified nucleic acid analogues via the palladium-
catalyzed cross-coupling reactions.
The extensive progress in exploration of scope of the reactants
that can be coupled using transition metals was not, however,
paralleled by the development of new catalytic systems. In a
majority of cases, Pd(PPh3)4 was used as a catalyst, as in original
procedures reported by Hirao in the early 1980s.4-6 Among a
few exceptions are reports on using other palladium sources
(e.g., Pd(OAc)2,10,18 Pd(PPh3)2Cl221) or different ligands (dppp,22
dppb,23 dppf20); however, the changes introduced were the result
Introduction
Organometallic chemistry has been one of the most rapidly
growing areas of chemistry over the past decades. Among
various chemical transformations catalyzed by transition metals,
cross-coupling reactions became an irreplaceable tool in organic
synthesis, especially since, in addition to the traditional carbon-
carbon bond formation,1 a new field of a cross-coupling with
heteroatom nucleophiles emerged.2 Although, the pioneering
work by the Buchwald and Hartwig groups on nitrogen
nucleophiles3-5 in the mid-1990s is usually recognized as the
beginning of this kind of chemistry, the first report on the
palladium-catalyzed coupling of vinyl bromides with H-phos-
phonates as nucleophiles appeared in 1980.4 This reaction was
further extended by other researchers to aryl halides6 and
triflates,7 as well as to vinyl triflates.8 On the side of nucleo-
philes, phosphinates,9 including H-phosphinates,10 phosphine
oxides,11 phosphines,12 and boranophosphines13 were success-
fully employed as substrates for this kind of coupling.
* To whom correspondence should be addressed. E-mail: js@
organ.su.se. Telephone: (+46) 0816 2485. Fax: (+46) 0815 4908.
† Stockholm University.
‡ Polish Academy of Sciences.
(1) Metal-catalyzed Cross-coupling Reactions; Wiley-VCH: Weinheim,
1998.
(14) Recent advances in organometallic chemistry directed towards
organic synthesis. Pure Appl. Chem. 2004, 76, No 3, 453-695.
(15) Schwan, A. L. Chem. Soc. ReV. 2004, 33, 218-224.
(16) Kurreck, J. Eur. J. Biochem. 2003, 270, 1628-1644.
(17) Johansson, T.; Stawinski, J. Chem. Commun. 2001, 2564-2565;
Zmudzka, K.; Johansson, T.; Wojcik, M.; Janicka, M.; Nowak, M.;
Stawinski, J.; Nawrot, B. New J. Chem. 2003, 27, 1698-1705. Johansson,
T.; Stawinski, J. Nucleosides Nucleotides Nucleic Acids 2003, 22, 1459-
1461. Lave´n, G.; Stawinski, J. Collection Symposium Series 2005, 7, 195-
199.
(2) Prim, D.; Campagne, J. M.; Joseph, D.; Andrioletti, B. Tetrahedron
2002, 58, 2041-2075.
(3) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1348-1350. Driver, M. S.; Hartwig, J. F. J. Am. Chem.
Soc. 1995, 117, 4708-4709.
(4) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Tetrahedron Lett.
1980, 21, 3595-3598.
(5) Hirao, T.; Masunaga, T.; Yamada, N.; Agawa, T. Bull. Chem. Soc.
Jpn 1982, 55, 909-913.
(6) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Synthesis 1981,
56-57.
(18) Abbas, S.; Hayes, C. J. Synlett 1999, 1124-1126.
(19) Abbas, S.; Hayes, C. J.; Worden, S. Tetrahedron Lett. 2000, 41,
3215-3219.
(7) Lu, X.; Zhu, J. Synthesis 1987, 726-727.
(8) Holt, D. A.; Erb, J. M. Tetrahedron Lett. 1989, 30, 5393-5396.
(9) Xu, Y.; Li, Z.; Xia, J.; Guo, H.; Huang, Y. Synthesis 1983, 377-
378; Xu, Y.; Zhang, J. Synthesis 1984, 778-780.
(10) Lei, H.; Stoakes, M. S.; Schwabacher, A. W. Synthesis 1992, 1255-
1260.
(20) Abbas, S.; Hayes, C. J. Tetrahedron Lett. 2000, 41, 4513-4517.
Lera, M.; Hayes, C. J. Org. Lett. 2000, 2, 3873-3875. Abbas, S.; Bertram,
R. D.; Hayes, C. J. Org. Lett. 2001, 3, 3365-3367.
(21) Schuman, M.; Lopez, X.; Karplus, M.; Gouverneur, V. Tetrahedron
2001, 57, 10299-10307.
(11) Xu, Y.; Li, Z.; Xia, J.; Guo, H.; Huang, Y. Synthesis 1984, 781-
782.
(12) Gilbertson, S. R.; Fu, Z.; Starkey, G. W. Tetrahedron Lett. 1999,
40, 8509-8512.
(13) Oshiki, T.; Imamoto, T. J. Am. Chem. Soc. 1992, 114, 3975-3977.
(22) Kurz, L.; Lee, G.; Morgans, D., Jr.; Waldyke, M. J.; Ward, T.
Tetrahedron Lett. 1990, 31, 6321-6324.
(23) Yan, Y.-Y.; RajanBabu, T. V. J. Org. Chem. 2000, 65, 900-906.
Bringmann, G.; Wuzik, A.; Breuning, M.; Henschel, K.; Peters, K.; Peters,
E.-M. Tetrahedron: Asymmetry 1999, 10, 3025-3031.
10.1021/om700797k CCC: $37.00 © 2007 American Chemical Society
Publication on Web 10/24/2007

Pd(0)-Catalyzed Phosphorus-Carbon Bond Formation
Organometallics, Vol. 26, No. 24, 2007 5841
entries 5, 11, and 12).27 Unfortunately, in the case of phosphorus
nucleophiles acidic additives are incompatible with the reaction
systems due to high basicity of the generated phosphorus(III)-
centered anions; however, use of the halides (Table 1, entries
7-10) or acetate ions (Table 1, entry 6) remained a viable
alternative. Jutand and Amatore investigated the influence of
halides and acetate only on the oxidative addition step,24,26 but
we assumed that these anionic species may coordinate also to
the palladium(II) species, thus influencing as well rates of the
second step in the catalytic cycle, namely, ligand substitution
by the phosphorus nucleophile (Scheme 1).
Scheme 1. Mechanism of Palladium-Catalyzed
Cross-Coupling between Aryl Halide and H-Phosphonatea
In this paper we present our studies on different palladium
sources with respect to their ability to catalyze the cross-coupling
reaction between phenyl halides and diethyl H-phosphonate.
Additionally, effects of the added halide and acetate ions on
rates of the investigated reactions were studied using 31P NMR
spectroscopy, and mechanistic explanations for the observed
variations in catalytic efficiency of the reaction systems gener-
ated from different palladium precursors are provided.
Results and Discussion
Pd(0)-based catalysts that are required for palladium-catalyzed
cross-coupling reactions can be either prepared from pure Pd-
(0) compounds or generated in situ from the appropriate Pd(II)
precursors. Using various sources of palladium may lead to
reagent systems that differ in their catalytic efficiency due to
the presence of differently ligated Pd(0) species.
a Depending on palladium source and additives G1, G1′ ) L (PPh3),
dba, X-, OAc-, solvent; G2 ) X-, OAc-, solvent.
Table 1. Reactivity of Palladium(0) Complexes in Oxidative
Addition with Iodobenzene as a Function of the Palladium
Precursors and Various Additives (L ) PPh3)a
Comparison of Different Palladium Sources. The most
commonly used palladium sources in the cross-coupling and
the Heck reactions are Pd(PPh3)4, Pd(dba)2, Pd(OAc)2, and
PdCl2. The former two already contain palladium(0), whereas
the other two compounds are palladium(II) salts that must be
reduced prior entering the catalytic cycle. In the case of Pd-
(OAc)2, the added phosphine ligands usually play the role of a
reducing agent,28,29 while PdCl2 or its ligated form PdIIL2Cl2
can be reduced by tertiary amines30 or the organometallic
nucleophile itself.31
For the purpose of our study we chose iodobenzene and
bromobenzene as model aryl halides and diethyl H-phosphonate
((EtO)2P(O)H) as the phosphorus nucleophile. All four pal-
ladium sources were used with an appropriate amount of PPh3
as a ligand.32 The reactions were carried with 10 mol % of a
catalyst loading, in THF at 60 °C using Et3N as a base (Scheme
2). The progress of the reactions was monitored by 31P NMR
spectroscopy, and the obtained results are summarized in Table
2.
reactive species
(S ) solvent)
K )
obs (M-1s-1
in THF (DMF)
entry
Pd(0) precursor
b
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd0L4
SPd0L2
16c (16)c (25)d
(21)d
Pd0L4+AcO-
Pd0L2(OAc)-
Pd0L2(OAc)-,H+
Pd0L2(OAc)-
Pd0L2(OAc)-,H+
Pd0L2(OAc)-
Pd0L2Br-
Pd(OAc)2 +5L
(41)d
Pd(OAc)2 +5L +3Et3N
Pd(OAc)2 +3L
(22)d
(140)d
(65)d
Pd(OAc)2 +3L +3Et3N
PdBr2L2 +2e
400c
-
PdBr2L2 +2e +nBr-
PdCl2L2 +2e
Pd0L2Br2
50c
Pd0L2Cl-
530c
-
PdCl2L2 +2e +nCl-
PdCl2L2 +2e +50Li+
PdCl2L2 +2e +Zn2+
Pd0(dba)2 + 2L
Pd0L2Cl2
72c
Pd0L2Cl,Li
1320c
1480c
2.7c (1.9)c
Pd0L2Cl,ZnCl
b
SPd0L2
a All data from refs 24 and 25. bTransient species present at trace
c
d
concentration. 20 °C. 25 °C.
of screening with various reaction conditions rather than a better
understanding of the underlying mechanisms.
In this context, stimulated by mechanistic reports by Jutand
and Amatore on the Pd-catalyzed reactions,24-26 we set out to
perform a comparative study of different palladium(0) precursors
to evaluate their efficiency in promoting the P-C bond
formation and to explore the effect of anionic additives on these
reactions. The latter possibility was suggested by Jutand and
Amatore, who have shown that rates of oxidative additions, a
common step for all cross-coupling reactions (Scheme 1), were
strongly influenced by species brought into the reaction mixture
with the palladium source, or by external additives, such as
halide or acetate ions, dba, bases, and Lewis acids (Table 1).
It is clearly visible from the data presented in Table 1 that
the highest rates of the oxidative additions were achieved in
the presence of Brønsted and, especially, Lewis acids (Table 1,
For both bromo- and iodobenzene the shortest reaction times
were found when the reaction was carried out in the presence
of a catalyst generated from Pd(OAc)2. Pd(PPh3)4, a catalyst
(27) Catalytic effect of halides in cross-coupling reactions was first
reported by T. Jeffery (Jeffery, T. J. Chem. Soc., Chem. Commun. 1984,
1287-1288). See also ref 38 for the use of halides in other cross-couplings
and Heck reactions.
(28) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992,
11, 3009-3013. Amatore, C.; Jutand, A.; Thuilliez, A. Organometallics
2001, 20, 3241-3249.
(29) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A. Organometallics
1995, 14, 1818-1826.
(30) Ziegler, C. B., Jr.; Heck, R. F. J. Org. Chem. 1978, 43, 2941-
2946.
(31) Negishi, E. I.; Takahashi, T.; Akiyoshi, K. J. Chem. Soc., Chem.
Commun. 1986, 1338.
(24) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254-
(32) We decided to generate PdII(PPh3)2Cl2 complex in situ from PdCl2
and 2 equiv of PPh3 rather than to use premade complex. According to our
observations (31P NMR) the complex is formed quantitatively within 30
min in THF at 60 °C and is smoothly reduced with Et3N in the presence of
an aryl halide.
278.
(25) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc 1991, 113,
8375-8384.
(26) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314-321.

5842 Organometallics, Vol. 26, No. 24, 2007
Kalek and Stawinski
Scheme 2. Model Cross-Coupling Reaction Used in the
Study
that the reaction is not quenched at the level of the Pd(II) species.
As the reaction proceeded, the signal from PdII(PPh3)2(OAc)2
gradually decreased and a new resonance due to Ph3PO (δP )
23.9 ppm), indicating that the palladium reduction occurred,
was formed. However, in contrast to the reference reaction that
was run in the absence of the H-phosphonate diester, the broad
peak due to the reduced Pd0(PPh3)2(OAc)- species (δP ) -4.7
ppm)29 did not appear, but instead a new signal at 95.5 ppm
emerged. The intensity of this new peak grew with time at the
expense of the H-phosphonate signal. Integration of the signal
at 95.5 ppm in relation to time showed that it was always
approximately two times bigger then the signal of Ph3PO. In
Table 2. Comparison of Different Palladium Sources in a
Cross-coupling Reaction between (EtO)2P(O)H and Bromo-
or Iodobenzene (Scheme 2)a
1
1
the H-coupled 31P NMR spectra no JPH coupling constant
characteristic for H-phosphonates was present, indicating a lack
of the P-H bond.
As for the chemical reactivity of an intermediate resonating
at 95.5 ppm, the addition of excess of iodobenzene to the
reaction mixture at 60 °C did not result in any changes in the
31P NMR spectrum over 1 h, meaning that this species did not
undergo oxidative addition. However, upon addition of 20 equiv
of PPh3 the intensity of the signal at 95.5 ppm started slowly to
decrease with time, demonstrating the complex was probably a
Pd(0) species in an equilibrium with Pd0(PPh3)n complexes.33
Additionally, for the stoichiometric reaction, when Pd(OAc)2,
iodobenzene, and the H-phosphonate diester were present in
equimolar amounts, the intermediate resonating at 95.5 ppm was
not formed and the reaction proceeded to the desired product,
diethyl phenylphosphonate, even when the reduction of Pd-
(OAc)2 with 3 equiv of PPh3 was carried out in the presence of
the H-phosphonate.
a Experimental conditions: 0.1 M (EtO)2P(O)H, 1.1 equiv of Ph-X, 1.2
b
equiv of Et3N, THF, 60 °C, 10 mol % Pd. A 15 min palladium reduction
performed prior to the addition of Ph-X and (EtO)2P(O)H.
commonly used for this purpose, gave slightly longer reaction
times, while using Pd(dba)2 as the palladium source resulted in
the slowest reactions (Table 2). It is important to note that in
the instance of Pd(OAc)2 it was necessary to perform the
palladium reduction prior to the addition of phenyl halide and
(EtO)2P(O)H; otherwise no product (diethyl phenylphosphonate)
was formed. Somewhat surprisingly, also no product formation
was observed with PdCl2 used as a palladium source, irrespective
of how the reduction was carried out.
All these observations allow us to propose a plausible
mechanism explaining the behavior of the catalytic system
generated from Pd(OAc)2 (Scheme 3). In the case of performing
the reaction with a preceding palladium reduction, the ordinary
reaction pathway is followed (path A in Scheme 3).29 In this
instance, the intermediate Pd0(PPh3)2(OAc)- formed is resistance
to complexation by diethyl H-phosphonate, but it undergoes an
oxidative addition with phenyl halide and, thus, may be involved
in the catalytic cycle. However, if the palladium reduction is
performed in the presence of the excess of (EtO)2P(O)H, the
H-phosphonate may intercept the short-living, low-ligated
intermediate Pd0(PPh3)(OAc)-,29 forming a complex (δP ) 95.5
ppm),34 which is unreactive toward phenyl halide in the
oxidative addition and, thus, cannot enter into the catalytic cycle
(path B, Scheme 3).35 Under stoichiometric reaction conditions,
when the palladium catalysts and the H-phosphonate diester are
present in equimolar (or close to it) amounts, the intermediate
resonating at 95.5 ppm is not formed and the reaction proceeds
to the desired product, diethyl phenylphosphonate (Scheme 2),
even when the reduction of Pd(OAc)2 with a phosphine is carried
out in the presence of the H-phosphonate. These indicate that
the low-ligated intermediate Pd0(PPh3)(OAc)- formed during
the reduction of Pd(OAc)2 can be intercepted by the H-
phosphonate only when the latter is present in large excess, as
The observed differences in efficiency of the catalytic systems
generated from Pd(PPh3)4, Pd(OAc)2, and Pd(dba)2 are in
agreement with the reactivity of the corresponding Pd(0) species
in the oxidative addition step (Table 1) of the investigated
reactions. However, the reason why the catalytic system
generated from PdCl2 was inactive in the studied cross-coupling
reactions remained unclear. Also, the phenomenon that when
the reduction of Pd(OAc)2 was carried out in the presence of
an aryl halide and the H-phosphonate diester, no product
formation was observed seemed puzzling. To address these
issues we decided to perform more detailed mechanistic
investigations using 31P NMR spectroscopy.
Complexation of the Generated Pd(0) Species by Diethyl
H-Phosphonate. The Pd(OAc)2 Case. Since it is known that
neither Et3N nor aryl halides interfere with the reduction of PdII-
(OAc)2 by PPh3 to form Pd0(PPh3)2(OAc)-, a reactive species
involved in the oxidative addition step,29 then it was apparent
that (EtO)2P(O)H prevented its formation or somehow deacti-
vated it.
First we checked if diethyl H-phosphonate can form com-
plexes with PdII(OAc)2. Since reduction of PdII(OAc)2 by PPh3
is an intramolecular reaction that involves intermediacy of PdII-
(PPh3)2(OAc)2,29 a competing complexation by the H-phospho-
nate present could prevent formation of this species and,
consequently, the palladium reduction. To this end, to a THF
solution of Pd(OAc)2, 10 equiv of the H-phosphonate were
added, and the reaction mixture was checked by 31P NMR
spectroscopy. Unfortunately, in neither the presence nor the
absence of Et3N, no additional resonances, except those of the
(33) Due to a rapid exchange of the phosphine moiety, only one weighed
average signal at δP ) -4.8 ppm for these complexes and free PPh3 was
observed.
(34) Structures for an intermediate resonating at δP ) 95.5 shown in
Scheme 3 and the related intermediates in Scheme 5 are only tentative.
These, and other low ligated intermediates discussed in this paper are, most
likely stabilized Via coordination of solvent molecules (that are omitted
from the structures) and may have geometries different from those shown
in the schemes.
H-phosphonate diester (δP ) 6.9 ppm, 1JPH ) 650 Hz,31JPH
)
8.2 Hz, dt), could be detected. However, when similar experi-
ments were repeated with the added PPh3 (3 equiv), the PdII-
(PPh3)2(OAc)2 complex (δP ) 14.9 ppm) was smoothly formed
without any interference from the H-phosphonate, which meant
(35) One should note that the Pd0(PPh3)(OAc)- species apparently cannot
be formed during the reductive elimination step of the catalytic cycle;
otherwise, the H-phosphonate present would intercept it and arrest the
catalytic reaction.

Pd(0)-Catalyzed Phosphorus-Carbon Bond Formation
Organometallics, Vol. 26, No. 24, 2007 5843
Scheme 3. Formation of Catalytically Active Pd(0) Complex from Pd(OAc)2 and PPh3 (Path A) and Suppression of Its
Formation in the Presence of (EtO)2P(O)H Excess (Path B)
Scheme 4. Behavior of Pd(dba)2 in the Presence of PPh3
it is the case for the catalytic reaction. Indeed, we found that
even with a 4 molar excess of (EtO)2P(O)H (it corresponds to
and/or (EtO)2P(O)H
a catalytic reaction with 25% Pd), the reduction of Pd(OAc)2
could be carried out in the presence of the H-phosphonate
without compromising the efficiency of the overall cross-
coupling reaction.
The Pd(dba)2 Case. The complexation of palladium(0) by
H-phosphonate diesters or secondary phosphine oxides is a
known phenomenon,36 and in many cases Pd(dba)2 is used as
the palladium source to obtain such complexes.36,37 Although,
some of the H-phosphonate Pd(0)-ligated species are able to
undergo oxidative addition and thus catalyze cross-coupling
reactions,37 apparently the one with (EtO)2P(O)H as a ligand is
not, as it was discussed above. However, in the studied cross-
coupling reaction (Scheme 2), when Pd(dba)2 was used as the
(OAc)2 suggested that there were no other ligands, except those
palladium source (Table 2, entry 3), a full conversion of the
of H-phosphonates and solvent molecules, associated with the
starting material into diethyl phenylphosphonate was observed,
palladium.
indicating that apparently complexation of the Pd(0) species by
The PdCl2 Case. Finally, we studied the possibility of
the H-phosphonate diester did not occur in this instance.
palladium(0) complexation by the diethyl H-phosphonate when
Indeed, in the 31P NMR spectrum of a solution prepared by
the PdCl2 was used as a palladium source. As it is apparent
dissolving in THF solid Pd(dba)2, PPh3 (2 equiv), and (EtO)2P-
from Table 2 (entry 4), the system based on PdCl2 was
(O)H (10 equiv), only the signals characteristic to Pd0(dba)-
inefficient in promoting the investigated cross-coupling reac-
tions. In light of the previous discussion, the most likely reason
(PPh3)2 (δP ) 25.3 and 27.2 ppm)38 were present. However, in
the absence of the phosphine, the peak at 95.5 ppm appeared,
for this was the formation of a catalytically inactive Pd(0)
indicating formation of the Pd(0) H-phosphonate complex.
H-phosphonate complex.
Similarly as for Pd(OAc)2, once this species was formed, it was
To check this hypothesis, PdCl2, PPh3 (2 equiv), Et3N (10
persistent to recomplexation by the added PPh3 (2 equiv).
equiv), and (EtO)2P(O)H (10 equiv) were dissolved in THF,
Our findings regarding the behavior of the catalytic system
and progress of the reaction was followed by 31P NMR
derived from Pd(dba)2 are summarized in Scheme 4. It seems
spectroscopy. Initially, the formation of PdII(PPh3)2Cl2 could
that, in a THF solution, Pd(dba)2 efficiently undergoes ligand
be observed (δP ) 23.6 ppm); however, as the reduction process
progressed, concentration of this species gradually decreased
exchange with PPh3, forming catalytically active species Pd0-
(dba)(PPh3)2, even in the presence of a large excess of (EtO)2P-
and simultaneously two new signals at 81.4 and 95.5 ppm, in
(O)H. Consequently, this reaction system worked under both
the approximate ratio 3:2, appeared. The signal at 95.5 ppm
catalytic and stoichiometric conditions, although rates of the
was assigned to the already discussed Pd(0) H-phosphonate
cross-coupling reactions were rather low (Table 2). On the other
complex, and the one at 81.4 ppm could originate from a similar
hand, when the phosphine was absent, the dba ligands were
species but having additionally one Cl- ion ligated.
replaced by two H-phosphonate molecules forming a complex
The following experiment was carried out to verify this
assumption: the Pd(0) diethyl H-phosphonate complex (δP )
95.5 ppm) was generated from Pd(dba)2 and (EtO)2P(O)H in
resonating at 95.5 ppm in the 31P NMR spectrum. Identical
chemical shifts of this complex and the one obtained from Pd-
THF, as described in the previous section. To this mixture, a
(36) Ackermann, L. Synthesis 2006, 1557-1571.
solution of n-Bu4N+Cl- in THF was added in small portions,
(37) Ackermann, L.; Althammer, A. Org. Lett. 2006, 8, 3457-3460.
and a 31P NMR spectrum was registered after each addition.
As expected, a gradual disappearance of the signal at 95.5 ppm
(38) Amatore, C.; Jutand, A. Coord. Chem. ReV. 1998, 178-180, 511-
528.

5844 Organometallics, Vol. 26, No. 24, 2007
Kalek and Stawinski
a
Scheme 5
a (a) Formation of Pd(0) diethyl H-phosphonate complexes from PdCl2 as the palladium source. (b) Formation of Pd(0) diethyl H-phosphonate
complexes ligated with Cl- (putative structures).
Table 3. Effect of Anionic Additives on the Reaction Times
of (EtO)2P(O)H with Bromo- or Iodobenzene (Scheme 2)a
and formation of the signal at 81.4 ppm were observed. With
an increasing concentration of Cl-, also additional signals at
101.4 and 84.1 ppm appeared, and after addition of a total 20
equiv of Cl-, the latter signal was the only one remaining, except
that from the excess of (EtO)2P(O)H (peak at δP ) 6.9
ppm).These results can be interpreted in the following way.
Using PdCl2 as the palladium source leads to the formation of
a complex resonating at 95.5 ppm (Scheme 5a) that, at the
concentration of Cl- brought into the system with PdCl2, is
partially ligated by a single chloride ion, giving rise to an
additional resonance signal at 81.4 ppm (3:2 ratio). With the
added chloride anions, there is a possibility to form other Pd-
(0) diethyl H-phosphonate complexes ligated by more Cl-.
Putative structures of such complexes, a dinuclear (resonating
at 101.4 ppm) and mononuclear one (resonating at 84.1 ppm),
are presented in Scheme 5b.
a Experimental conditions: 0.1 M (EtO)2P(O)H, 1.1 equiv of Ph-X, 1.2
equiv of Et3N, THF, 60 °C, 10 mol % Pd, anions were added as
corresponding n-Bu4N+ salts. bA 15 min palladium reduction performed
prior to addition of Ph-X and (EtO)2P(O)H.
All these Pd(0) H-phosphonate complexes were unreactive
in the oxidative addition of aryl halides; therefore PdCl2 seems
to be incompatible as the palladium source in the cross-coupling
with the H-phosphonate is investigated, under neither catalytic
nor stoichiometric conditions.
given anionic part was used to suppress competition from these
Br- or I- anions. By having such high anion concentrations,
formation of the most reactive Pd(0) species ligated with a single
halide is most likely compromised (Table 1, entry 7 vs 8 for
Br- and entry 9 vs 10 for Cl-); however, we considered the
homogeneity of the reacting forms to be more important at the
current stage of these studies. As it is apparent from data in
Table 3, upon additions of Cl-, Br-, and OAc-, the times for
completion of all the reactions investigated became shorter,
approximately to the same extent, irrespective of the palladium
source used. The most notable effect was that of the acetate
ions, for which a remarkable acceleration (Table 3, entry 7),
much higher than those for chlorides or bromides (Table 3,
entries 2, 5 and 3, 6 respectively), was observed. These
surprising results suggested that the role of the added anions
was not limited to the oxidative addition but that these additives
also strongly influenced other steps in the catalytic cycle that
might ultimately lead to the change of a rate-determining step.
Effect of Anion Additives on the Rate of the Cross-
Coupling between Phenyl Halides and Diethyl H-Phospho-
nate. After having established the phenomenon of Pd(0)
complexation with diethyl H-phosphonate, and how and when
it may interfere with the cross-coupling reactions, we investi-
gated the effects of different anionic additives on the rate of
the reaction presented in Scheme 2. Due to incompatibility of
the PdCl2 reagent system and low reactivity of Pd(dba)2 in the
investigated reactions (Table 2), further studies were performed
only with Pd(PPh3)4 and Pd(OAc)2 as the palladium sources.
According to the data shown in Table 1, the oxidative addition
step of the catalytic cycle is accelerated in the presence of Cl-,
Br-, and OAc-, due to formation of very reactive, electron-
rich anionic Pd(0) species ligated with these anions. Taking into
account that bromides and iodides are produced in the course
of the reactions with bromobenzene and iodobenzene, respec-
tively, a 10-fold excess of tetra-n-butylammonium salts with a

Pd(0)-Catalyzed Phosphorus-Carbon Bond Formation
Organometallics, Vol. 26, No. 24, 2007 5845
Scheme 6. Formation of Three Pd(II) Species That Might Be Involved in Ligand Exchange Reaction with the H-Phosphonate
Qualitative Comparison of Reactivity of Different Phe-
nylpalladium(II) Species with (EtO)2P(O)H in the Ligand
Substitution Step. Since the data from Table 3 cannot be
explained on the grounds of rates of the oxidative additions
(Table 1) or the reductive eliminations (the same intermediate
for all the reactions, Scheme 1), we assumed that the observed
differences must originate from distinct reactivities of the Pd-
(II) species during the ligand substitution step.
for the reactivity of a single reactive species, on two counts.
First, they resemble the real catalytic reaction conditions, with
all other components being present, and with both the “initial”
and the “secondary” Pd(II) complexes having a possibility of
reacting with the H-phosphonate. Second, since the Pd(II)
complexes are in equilibrium, this method would provide
information about relative rates of the complexes’ equilibration
and their reactions with the H-phosphonate.
First, a 1:1 mixture of Pd(II) complexes ligated with I- and
Br- was prepared, and the reaction of the produced species with
diethyl H-phosphonate was followed by 31P NMR spectroscopy
(Figure 2a). To this end, PhPdII(PPh3)2I was generated in THF
at 60 °C (1 min) from equimolar amounts of iodobenzene and
Pd(PPh3)4, and to these, 0.5 equiv Br- (as n-Bu4N+ salt) was
added. After equilibration at 60 °C for 15 min, a 1:1 mixture
of PhPdII(PPh3)2I and PhPdII(PPh3)2Br was obtained.42 At this
point 10 equiv Et3N was added, followed by 10 equiv of
(EtO)2P(O)H, and the mixture was incubated at 60 °C (Figure
2a). It was clearly visible that the peak due to PhPdII(PPh3)2Br
disappeared faster than that of PhPdII(PPh3)2I, indicating higher
reactivity of the former species under the reaction conditions.
The complex with ligated bromide almost completely disap-
peared within 45 min after addition of the H-phosphonate, while
its iodide counterpart was still present in the solution.
Similar experiments were performed with ca. 1:1 mixtures
of PhPdII(PPh3)2I and PhPdII(PPh3)2Cl (Figure 2b) and PhPdII-
(PPh3)2I with PhPdII(PPh3)2(OAc) (Figure 2c). Both PhPdII(PPh3)2-
Cl and PhPdII(PPh3)2(OAc) complexes appeared to be more
reactive than PhPdII(PPh3)2I; however, a huge difference in
reactivity between these two species was observed. While
PhPdII(PPh3)2Cl displayed a comparable reactivity to that for
PhPdII(PPh3)2Br (Figure 2b vs 2a, respectively) as judged from
the rates of disappearance of their 31P NMR signals (ca 45 min),
the signal originating from PhPdII(PPh3)2(OAc) could not be
detected after 1 min (the time required to place NMR tube back
into the spectrometer and register the spectra) after addition of
(EtO)2P(O)H (Figure 2c). Unfortunately, due to almost identical
31P NMR chemical shifts of PhPdII(PPh3)2Br and PhPdII(PPh3)2-
Cl we were not able to determine relative reactivities of these
two palladium(II) species.
The square planar palladium(II) complexes formed in the
course of the oxidative addition, depending on the kind of
anionic additives present, can be differently ligated24 and thus
may show different reactivities (Scheme 6). For example, the
initial Pd(II) complex, formed directly in the oxidative addi-
tion,39 can bear an acetate group brought from the Pd(0) complex
(G2 ) OAc in Pd(II) complex if G1 ) OAc in the preceding
Pd(0) complex)40 or alternatively a halide brought from Ar-X,
if Pd(0) was ligated by another halide [G2 ) X in Pd(II) complex
if G1 ) Cl or Br in the preceding Pd(0) complex].41 In the
presence of anionic additives, G2 in the initial Pd(II) complex
may undergo exchange, probably via a dissociative mechanism
or/and produce the cationic PhPdII(PPh3)2 complex Via a
+
dissociative pathway.40 Therefore, during a cross-coupling
reaction, three distinct Pd(II) species might be involved in the
formation of a phenyl-H-phosphonate-palladium(II) intermedi-
ate, from which reductive elimination occurs. These are the
“initial” Pd(II) complex formed in the oxidative addition,
+
cationic PhPdII(PPh3)2 intermediate, and “secondary” Pd(II)
complex ligated by another anion present in the reaction mixture.
Scheme 6 summarizes the Pd(0) and Pd(II) species that can be
present in the reaction mixtures from Table 3.
To establish relative reactivities of the Pd(II) complexes
ligated with different anions in the reaction with (EtO)2P(O)H,
we performed 31P NMR investigations. We decided to generate
simultaneously two Pd(II) complexes, ligated with different
anions, and observed their decay upon addition of (EtO)2P(O)H.
Such competitive experiments have advantages over looking
(39) To be specific, a complex formed first in the oxidative addition is
assumed to be a trigonal bipyramid PhPdII(PPh3)2G1X that, in the presence
of a minute amount of free PPh3 (which is the case for Pd(PPh3)4 or Pd-
(OAc)2 + 3PPh3), quickly collapses to trans-PhPdII(PPh3)2G2 with the
expulsion of G1 or X. For details, see refs 24 (review), 40 (G1 ) OAc),
and 41 (G1 ) Cl).
(40) Amatore, C.; Carre´, E.; Jutand, A.; M’Barki, M. A.; Meyer, G.
Organometallics 1995, 14, 5605-5614.
(41) Amatore, C.; Jutand, A.; Suarez, A. J. Am. Chem. Soc. 1993, 115,
9531-9541.
(42) The affinity of anions to Pd(PPh3)2(Ph)-X decreases in the order
Cl- > Br- > I- ≈ OAc-, and large differences in equilibria constants
enable a practically quantitative replacement of the anion lower in the row
with the one which is higher. See also refs 24 and 40.

5846 Organometallics, Vol. 26, No. 24, 2007
Kalek and Stawinski
Figure 1. 31P NMR competition experiments between Pd(II) species ligated with different anions in reaction with (EtO)2P(O)H: (a) Br-
vs I-; (b) Cl- vs I-; (c) I- vs OAc-; (d) Br- vs OAc-; (e) Cl- vs OAc-; I- vs OAc- vs cationic species. Small signal at 23.7 ppm
originates from contamination with Ph3PO.
Attempted generation of mixtures of PhPdII(PPh3)2(OAc) with
PhPdII(PPh3)2Br and with PhPdII(PPh3)2Cl failed due to large
differences in the corresponding equilibrium constants,43 and
thus we had to use premade PhPdII(PPh3)2(OAc) as a starting
material (Figure 2d and 2e). In both cases the complex ligated
with OAc- displayed much higher reactivity than its halide
counterparts. Similarly as in the experiment shown in Figure
2c, the signal due to PhPdII(PPh3)2(OAc) disappeared within
the time required to register the 31P NMR spectrum (∼1 min),
again demonstrating a remarkably high rate of reaction between
this species and the H-phosphonate.
ensure a complete palladium reduction to take place. The
subsequent addition of iodobenzene (1 equiv) resulted in a rapid
reaction producing a mixture of the “initial” palladium(II)
complex PhPdII(PPh3)2(OAc) (δP ) 21.2 ppm) and a complex
with dissociated ligand PhPdII(PPh3)2+ (δP ) 21.5 ppm). After
15 min at 60 °C, the equilibrated reaction mixture contained
PhPdII(PPh3)2(OAc), PhPdII(PPh3)2I, and PhPdII(PPh3)2+ (Figure
2f) and the addition of (EtO)2P(O)H (10 equiv) caused a rapid
disappearance of both PhPdII(PPh3)2(OAc) and PhPdII(PPh3)2
+
species (31P NMR spectroscopy). The decay of the remaining
PhPdII(PPh3)2I was slow and roughly similar to that observed
in the previous experiments (Figure 2a and 2b). At this stage
of investigations we could not conclude if the rapid disappear-
ance of PhPdII(PPh3)2+ indicated that this species reacted directly
with the H-phosphonate or that it was involved in rapid
equilibrium with the highly reactive PhPdII(PPh3)2(OAc).43
Finally, we became interested in comparing the reactivity of
PhPdII(PPh3)2(OAc) with that of PhPdII(PPh3)2+ (Figure 2f). For
this purpose, Pd(OAc)2, PPh3 (3 equiv), and Et3N (10 equiv)
were dissolved in THF and incubated for 15 min at 60 °C, to
(43) Interestingly, PhPdII(PPh3)2(OAc) and PhPdII(PPh3)2+ showed com-
parable or lower reactivity to that of PhPdII(PPh3)2I in the reaction with
styrene (syn-insertion step of the Heck reaction). See also ref 41.
To sum up this part, the reactivity of the Pd(II) species in
the ligand substitution reaction with diethyl H-phosphonate

Pd(0)-Catalyzed Phosphorus-Carbon Bond Formation
Organometallics, Vol. 26, No. 24, 2007 5847
decreases in the following order (PhPdII(PPh3)2+), PhPdII(PPh3)2-
(OAc) . PhPdII(PPh3)2Cl, PhPdII(PPh3)2Br > PhPdII(PPh3)2I,
and in light of these, we can propose the following rationaliza-
tion for the results and the trends observed in Table 3.
Using Pd(OAc)2 as a palladium source in cross-coupling
reactions involving phosphorus nucleophiles should, in principle,
increase efficiency of the reaction, compared to that catalyzed
by Pd(PPh3)4, due to higher reactivity, in both the oxidative
addition and the ligand substitution steps, the generated
intermediates Pd0(PPh3)2(OAc)- and PhPdII(PPh3)2(OAc). How-
ever, in practice, both systems show similar efficiency in the
investigated reaction as it is apparent from entry 4 vs 1 in Table
3. This is apparently due to the fact that, in the course of the
reaction, the concentration of the halide anion released from
Ar-X builds up, and thus the amount of the initially formed
reactive species Pd0(PPh3)2(OAc)- and PhPdII(PPh3)2(OAc) is
rapidly depleted in the reaction mixture. As a result, the
efficiencies of both catalytic systems become similar, since the
initial acceleration observed in the case of a system based on
Pd(OAc)2 results only in a small shortening of the total reaction
time.
H-phosphonate, and aryl halides. Regarding the palladium
source, it was demonstrated that the best results were obtained
with Pd(OAc)2. When using this compound as a Pd(0) precursor,
a preceding palladium reduction must be performed to avoid
an interference from the complexation of the Pd(0) species by
the H-phosphonate. For the same reason PdCl2 turned out to be
inefficient in cross-coupling reactions, at least for the H-
phosphonate investigated.
This study also showed that it was possible to efficiently
accelerate the cross-coupling reactions via the addition of
different anions, e.g., halides or acetate, that strongly influenced
the ligand substitution step. It was also found that the reactivity
of the Pd(II) species in the ligand substitution reaction with
diethyl H-phosphonate decreased in the following order: PhPdII-
+
(PPh3)2 , PhPdII(PPh3)2(OAc) . PhPdII(PPh3)2Cl, PhPdII(PPh3)2-
Br > PhPdII(PPh3)2I.
Palladium(II) species ligated with the acetate ion exhibited
remarkably high reactivity, leading to an unprecedented ac-
celeration of the overall cross-coupling reaction between aryl
halides and H-phosphonate diesters. This phenomenon might
be of importance in synthetic organic chemistry, and further
studies are in progress in this laboratory.
Performing the reaction with Br- or Cl- as additives (Table
3, entries 2, 3, 5, and 6) leads to exclusive formation of Pd(0)
species ligated by these anions, and this results in an acceleration
at the level of the oxidative addition. The ligand substitution
step is also affected; however, since the reactivities of
PhPdII(PPh3)2Cl and PhPdII(PPh3)2Br are only slightly higher
than that of PhPdII(PPh3)2I, these have only a mediocre
contribution to the overall acceleration. Thus, it seems that using
Pd(OAc)2 together with the halide as additives (Table 3, entries
5 and 6) does not provide any advantages in terms of efficiency
but adds technical complicacy due to necessity of performing a
separate palladium reduction step.
Finally, when the acetate additive is used (Table 3, entry 7),
the reactive species Pd0(PPh3)2(OAc)- and PhPdII(PPh3)2(OAc)
are present throughout the reaction, accelerating both the
oxidative addition and the ligand substitution steps, and lend
themselves to a remarkable shortening of the cross-coupling
reaction time.
Experimental Section
Bromobenzene, n-Bu4NBr, iodobenzene, Pd(dba)2, PPh3 (all from
Aldrich), n-Bu4NCl, n-Bu4NOAc, Et3N (all from Alfa), Pd(PPh3)4
(Apollo Scientific), (EtO)2P(O)H (Janssen Chimica), PdCl2, and
Pd(OAc)2 (Lancaster) were commercial grades and were used
without further purification.
Complex PhPdII(PPh3)2(OAc) was prepared according to the
published procedure.40 THF was freshly distilled from sodium/
benzophenone under an Ar atmosphere.
All experiments were carried out under an Ar atmosphere in 10
mm NMR tubes equipped with septa, using standard Schlenk
techniques. NMR spectra were recorded on Bruker Avance II 500
MHz instrument. Chemical shifts are reported in ppm, relative to
2% H3PO4 solution in D2O (external standard).
The reactant ratios and the experimental conditions for the
investigated reactions are given in the appropriate tables and in
the text.
Conclusions
Acknowledgment. Financial support from the Swedish
Research Council is gratefully acknowledged.
In summary, we studied several aspects of the cross-coupling
reaction between a model phosphorus nucleophile, diethyl
OM700797K