Fast Suzuki-Miyaura cross-coupling reaction with hexacationic triarylphosphine Bn-dendriphos as ligand

Article abstract of DOI:10.1002/adsc.200700366

The application of hexa[(dimethylamino)-methyl]-functionalized triphenylphosphine (1) and its benzylammonium salt, Bn-Dendriphos (2), in the Suzuki-Miyaura cross-coupling of aryl bromides with arylboronic acids is described. The 3,5-bis[(benzyldimethylammonio)methyl] substitution pattern in 2 leads to a rate enhancement compared to both the non-ionic parent compound 1 and triphenylphospine (PPh₃) itself. At the same time, the resulting catalytic species are stable towards palladium black formation, even at a phosphine/palladium ratio of 1. These observations are attributed to the presence of a total of six ammonium groups in the backbone of the phosphine ligand, which presumably leads to an unsaturated phosphine-palladium complex.

Full text of DOI:10.1002/adsc.200700366

FULL PAPERS
DOI: 10.1002/adsc.200700366
Fast Suzuki–Miyaura Cross-Coupling Reaction with Hexacationic
Triarylphosphine Bn-Dendriphos as Ligand
Dennis J. M. Snelders,a Robert Kreiter,a Judith J. Firet,a Gerard van Koten,a
and Robertus J. M. Klein Gebbinka,*
a
Faculty of Science, Chemical Biology and Organic Chemistry. Utrecht University, Padualaan 8, 3548 CH Utrecht, The
Netherlands
Phone: (+31)-30-252-3120; fax: (+31)-30-252-3615; e-mail: r.j.m.kleingebbink@uu.nl
Received: July 25, 2007; Revised: September 28, 2007; Published online: January 4, 2008
Abstract: The application of hexa[(dimethylamino)- species are stable towards palladium black forma-
methyl]-functionalized triphenylphosphine (1) and its tion, even at a phosphine/palladium ratio of 1. These
benzylammonium salt, Bn-Dendriphos (2), in the observations are attributed to the presence of a total
Suzuki–Miyaura cross-coupling of aryl bromides with of six ammonium groups in the backbone of the
arylboronic acids is described. The 3,5-bis[(benzyldi- phosphine ligand, which presumably leads to an un-
methylammonio)methyl] substitution pattern in 2 saturated phosphine-palladium complex.
leads to a rate enhancement compared to both the
À
non-ionic parent compound 1 and triphenylphospine Keywords: C C coupling; Dendriphos; palladium;
(PPh3) itself. At the same time, the resulting catalytic phosphine; Suzuki–Miyaura reaction
Introduction
Dendriphos {[P
C
Recently, we developed a novel class of hexaionic bine a triarylphosphine core with a shell of six ammo-
phosphines derived from the hexa[(dimethylamino)- nium groups. The latter feature makes this series of
methyl]-functionalized triarylphosphine core molecule dendritic ligands very versatile, as it enables them to
1 [P(NCN)3, Figure 1], for which we coined the name act as phase-transfer agents and opens the way for
G
catalyst recovery by means of a biphasic work-up or
via nanofiltration. Both NMR and molecular model-
ling experiments suggested the use of these hexa-
cationic phosphines as bulky ligands.[1] At the same
time, based on the solubility range of these ligands,
applications in both H2O and MeOH, as well as in or-
ganic solvents, can be envisioned.
As our first investigation into the use of this class
of ligands in homogeneous catalysis, we applied Bn-
Dendriphos (2, R=Bn, soluble in MeOH) in the
Suzuki–Miyaura reaction, which is a widely used, Pd-
À
mediated C C coupling method, tolerating numerous
functional groups.[2] The latter feature makes this re-
action feasible for the preparation of, e.g., natural
products or pharmaceuticals.[3] Most of these reactions
apply aryl halides and boronic acids; boronic acids
being much less toxic and easier to handle than (main
group) organometallic compounds used in other
cross-coupling reactions.[4] Among the successful ex-
amples of catalysts for this reaction are ligand-free Pd
species[5] and Pd complexes using various types of li-
gands, such as N-heterocyclic carbenes[6] and sterically
constrained and electron-rich monodentate phosphine
Figure 1. Hexaamino- and hexaammonium-functionalized
triarylphosphines 1 and 2.
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Suzuki–Miyaura Cross-Coupling Reaction with Hexacationic Triarylphosphine Bn-Dendriphos
FULL PAPERS
ligands, such as bulky trialkylphosphines,[7] biarylphos-
phines[8] and ferrocenylphosphines.[9] In this report,
we present our first results concerning the application
of hexacationic triarylphosphine Bn-Dendriphos (2)
in this reaction and the remarkable rate-enhancing
effect of the 3,5-bis[(benzyldimethylammonio)methyl]
substitution pattern in its ligand structure.
Table 1. Selected catalytic data for the reaction of Eq. (1).
Results and Discussion
As model reaction we selected the coupling of 4-tolyl-
boronic acid and methyl 4-bromobenzoate giving
methyl 4-tolylbenzoic ester 3 [Eq. (1)]. Pd(dba)2 was
N
[a]
Time at which the GC yield reached 50%.
Yield of the cross-coupled product, determined by GC.
Pd black was formed.
No base was used.
[b]
[c]
[d]
tion in water.[5a,b] Similar results at very low catalyst
loadings were reported by de Vries et al.[5c,d] The use
of a phosphine ligand stabilizes the catalyst and can
used as palladium source and Na2CO3 (2 equivs. with prevent the formation of Pd black. Due to the inhibi-
respect to the aryl bromide) as base in a mixture of tory role played by the phosphine ligand in the case
methanol and water (9/1, v/v) at 658C. The hexaionic of PPh3,[4] the reaction is slowed down dramatically.
phosphine [P(NCN)3·Bn6]Br6 (2, B nD- endriphos) was Remarkably, the use of an equal amount of hexaionic
G
tested as donor ligand at 3, 1, 0.1, and 0.01 mol% of 2 does not show any decrease in reaction rate, while
Pd loading. The number of equivalents of phosphine still preventing Pd black formation. As a result of
per palladium center was varied from 4 down to 1. high activity combined with high stability, quantitative
Furthermore, hexaionic 2 was compared to the parent yield is obtained within 10 min, even at 0.1 mol% Pd
phosphine P
ACHTREUNG
actions were run in the absence of phosphine, base or
palladium source. The catalyst performance is ex- Pd concentration was lowered from 3, via 1 and 0.1 to
pressed as the time at which the coupling yield 0.01 mol% using each time four equivalents of 2
reached 50%, as well as the maximum obtained yield (Table 1, entries 1, 4, 7 and 8). These experiments
and the required reaction time (Table 1).
show that only at a concentration of 0.01 mol% Pd
These experiments show that 2 exhibited a behav- does the reaction rate start to drop. When the ratio of
iour that is dramatically different from that of the ligand 2 to Pd was decreased from 4:1 to 2:1 and 1:1
benchmark ligand PPh3. For example, when four at a Pd loading of 0.01 mol%, a slight increase in re-
equivalents of 2 were applied at 1 mol% Pd loading,
a quantitative yield was reached within ten minutes,
whereas in the case of PPh3 this took up to seven
hours. Neutral ligand 1 also gave a lower rate than
that found for hexaionic 2 (Figure 2), but performed
better than PPh3.[10]
Importantly, due to the activated nature of the aryl
bromide employed, the present benchmark reaction is
extremely fast. In fact, in the absence of any ligand, a
quantitative yield is obtained after 90 min at 3 mol%
Pd, even though rapid Pd black formation is ob-
served. At 0.01 mol% Pd, the ligand-free process re-
sulted in a similar activity, reaching a maximum yield
of 90% after 20 min. These results are in line with
those found by Bumagin et al., who reported a
ligand- and stabilizer-free, Pd-catalyzed Suzuki reac-
Figure 2. The effect of the ligand on the reaction of Eq. (1)
at 1 mol% Pd loading. In each case a phosphine/palladium
ratio of 4 was used.
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Dennis J. M. Snelders et al.
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Table 2. Catalytic data for the reaction of Eq. (2).
Figure 3. The effect of ligand/Pd ratio on the reaction of Eq.
(1) at 0.01 mol% Pd loading using Bn-Dendriphos.
action rate was seen, while at the same time still no
Pd black formation was observed (Figure 3).
To investigate the influence of the ammonium
groups in Bn-Dendriphos on the reaction, 2 was
tested in the absence of Pd (Table 1, entry 12). Am-
À
monium salt-promoted C C coupling reactions
with[11b] and without[11a] Pd were reported before. The
reported activities in the ꢁabsenceꢂ of Pd were recent-
ly rationalized by the presence of trace amounts of
metal in the applied base.[11c] In our case, however, no
conversion was observed in the absence of added Pd.
Therefore we believe that the activity observed origi-
[a]
Yield of the cross-coupled product, determined by GC
after 3 h of reaction time.
nates from a homogeneous Bn-Dendriphos-Pd com- though Pd black was never observed, the yield in-
plex. In previous studies it was noted that aryl halides creased only marginally by letting the reactions run
can be reduced by primary and secondary alcohols in for an additional 3 h. This suggests that our reaction
the presence of a Pd(0) source and a base.[8c,12] In our conditions need further optimization for coupling of
experiments, however, no detrimental effect of the more challenging substrates. We are currently per-
use of MeOH was observed.
forming these investigations.
The performance of our catalytic system was fur-
Our results clearly indicate that hexaionic phos-
ther probed by performing the reaction with several phine 2 can stabilize a Pd(0/II) center, without lead-
A
non-activated and deactivated aryl bromides, as well ing to inhibition of the reaction rate, as seen with the
as with some challenging arylboronic acids [Eq. (2) benchmark ligand PPh3. It can thus be concluded that
and Table 2].
2 has a very low inhibition factor.[13] This indicates
that 2 leads to a preferential formation of coordina-
tively unsaturated phosphine Pd(0) species. The rela-
tively small observed difference in activity between
high and low L:Pd ratios (Figure 3) supports this
view. Similar behaviour has been described for
bulky[7b] or bowl-shaped[14] phosphine ligands, but
never for phosphine ligands based on a triarylphos-
phine having a shell of ionic groups. Recently, an m-
carboxylic acid-functionalized triphenylphosphine
ligand (m-TPPTC) was reported, which showed in-
creased reactivity in Sonogashira cross-couplings com-
pared to its sulfonated analogue (TPPTS).[15] In this
The results in Table 2 show that several aryl boron- case however, the authors rationalize the results by
ic acids can be coupled with the same efficiency as the increased basicity of the ligand. The results for 1
observed for 4-tolylboronic acid. Changing the aryl and 2 are in line with the molecular modelling and co-
bromide, however, leads to a decrease in the observed ordination experiments on these ligands, reported
reaction rate. After 3 h of reaction time, moderate elsewhere.[1,16] Based on these studies we predicted
yields were obtained for most aryl bromides. Even enlarged cone angles and a bulky behaviour for 2. We
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Suzuki–Miyaura Cross-Coupling Reaction with Hexacationic Triarylphosphine Bn-Dendriphos
FULL PAPERS
3H, CH3); 13C NMR (300 MHz, acetone-d6): d=141.5,
135.7, 129.7 (ArC), 22.20 (CH3).
believe that in our case the Coulombic repulsion be-
tween neighbouring phosphine ligands acts as a
ꢁpseudo-bulkꢂ and facilitates dissociation of 2 from
the Pd center, allowing in situ formation of coordina-
tively highly unsaturated and catalytically active phos-
phine Pd(0) species.
GeneralProcedure for the Suzuki–Miyaura Reaction
Arylboronic acid (2.57 mmol), aryl bromide (2.33 mmol),
Na2CO3 (0.49 g, 4.6 mmol), Pd(dba)2 (3, 1, 0.1, or 0.01
G
mol% with respect to the aryl bromide) and phosphine
ligand 1, 2 or PPh3 [4, 2 or 1 equivalents with respect to the
Pd(dba)2], were placed in a vial under nitrogen. H2O
A
Conclusions
(1.0 mL) and MeOH (9.0 mL) were added and the vials
were placed in a pre-heated oil bath. At appropriate inter-
vals, samples (0.1 mL) were taken and worked-up by adding
1M NaOH (1.0 mL) and CH2Cl2 (1.5 mL) with thorough
mixing. The organic layer was used for GC-analysis, using
pentadecane as an internal standard. The aryl bromide, the
cross-coupled product and the internal standard were de-
tected by GC. No other (side) products were observed.
The monodentate, hexacationic triarylphosphine
ligand 2 leads, in combination with Pd(dba)2, to an ef-
ficient catalytic system for the Suzuki–Miyaura cross-
coupling reaction. From the comparison with the non-
ionic parent compound as well as the benchmark
ligand PPh3, the beneficial effect of the six ammoni-
um groups on the reaction rate is apparent. Lowering
A
the 2/Pd(dba)2 molar ratio from 4 to 1 resulted in a
E
slight increase of activity, without noticeable effect on
the stability of the palladium site in the complex. This
indicates a preferential formation of coordinatively
unsaturated Pd complexes, which is a property that
could be beneficial in a wide range of catalytic appli-
cations. Currently, we are further investigating the ap-
plication of 2 and other Dendriphos ligands[1] for the
catalytic conversion of more challenging substrates
such as aryl chlorides. Application of these ligands in
other metal-catalyzed transformations, are also envis-
aged.
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ExperimentalSection
GeneralRemarks
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G
G
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a
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A
wise and the mixture was allowed to warm up to room tem-
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dryness. The resulting crude product was purified by recrys-
tallization from H2O. Yield: 3.81 g (72%). 1H NMR
(300 MHz, acetone-d6): d=7.76 (d, 2H, JH,H =7.8 Hz, ArH),
7.16 (d, 2H, JH,H =7.2 Hz, ArH), 7.03 (s, 2H, OH), 2.32 (s,
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