Analogs of Grubbs' second generation catalyst with hydrophilic phosphine ligands: Phase transfer activation of ring closing alkene metathesis

Article abstract of DOI:10.1021/ol202548q

Analogs of Grubbs' second generation catalyst with hydrophilic phosphine ligands are synthesized, and those with Cy₂PCH₂CH ₂N(CH₃)₃⁺ Cl^- and Cy ₂PCHCH₂CH

Full text of DOI:10.1021/ol202548q

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6188–6191
Analogs of Grubbs’ Second Generation
Catalyst with Hydrophilic Phosphine
Ligands: Phase Transfer Activation of
Ring Closing Alkene Metathesis
Zhenxing Xi,†,‡ Hassan S. Bazzi,*,† and John A. Gladysz*,‡
Department of Chemistry, Texas A&M University at Qatar, P.O. Box 23874, Doha,
Qatar, and Department of Chemistry, Texas A&M University, P.O. Box 30012,
College Station, Texas 77842-3012, United States
gladysz@mail.chem.tamu.edu; bazzi@tamu.edu
Received September 25, 2011
ABSTRACT
Analogs of Grubbs’ second generation catalyst with hydrophilic phosphine ligands are synthesized, and those with Cy2PCH2CH2N(CH3)3þ Clꢀ and
Cy2PCHCH2CH2N(CH3)2þCH2 CH2 Clꢀ give much faster ring closing metatheses under CH2Cl2/aqueous or CH2Cl2/aqueous HCl biphasic as
opposed to CH2Cl2 monophasic conditions. This is attributed to rapid phase transfer of the dissociated ligand to the aqueous phase, where under
acidic conditions it is protonated.
Hydrophilic ligands are usually employed to solubilize
a metal complex, typically a catalyst or precatalyst, in
water.1 Particular attention has been given to hydro-
philic phosphine ligands.2 Accordingly, several water-
soluble analogs of Grubbs’ first generation alkene metathesis
catalyst (1)3 and related species4 have been reported and
employed in aqueous phase chemistry. Some examples are
depicted in Figure 1. Additional types of water-soluble
ruthenium metathesis catalysts, and metatheses carried
out in or in the presence of water, have been reviewed.5
† Texas A&M University at Qatar.
‡ Texas A&M University.
(1) Shaughnessy, K. H. Chem. Rev. 2009, 109, 643.
(2) (a) Pinault, N.; Bruce, D. W. Coord. Chem. Rev. 2003, 241, 1. (b)
€
Prasang, C.; Bauer, E. B. In Phosphorus Ligands in Asymmetric Cata-
€
lysis; Borner, A., Ed.; Wiley-VCH: Weinheim, 2008; Vol. 3, p 917. (c)
Snelders, D. J. M.; van Koten, G.; Klein Gebbink, R. J. M. Chem.;Eur.
J. 2011, 17, 42.
(3) (a) Grubbs, R. H. In Aqueous Organometallic Chemistry and
Figure 1. Some water-soluble ruthenium metathesis catalysts.
ꢀ
ꢀ
Catalysis; Horvath, I. T., Joo, F., Eds.; Kluwer: The Netherlands, 1995; p
15. (b) Lynn, D. M.; Mohr, B.; Grubbs, R. H.; Henling, L. M; Day,
M. W. J. Am. Chem. Soc. 2000, 122, 6601.
However, there are further potential applications for
ligands that are soluble in water or a phase orthogonal to
the reaction medium. Forexample, withmany metal-based
catalyst precursors, a ligand must first dissociate before the
catalytic cycle can be entered. The reverse reaction often
(4) (a) Gallivan, J. P.; Jordan, J. P.; Grubbs, R. H. Tetrahedron Lett.
2005, 46, 2577. (b) Hong, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006,
128, 3508.
(5) Burtscher, D.; Grela, K. Angew. Chem., Int. Ed. 2009, 48, 442;
Angew. Chem. 2009, 121, 450.
r
10.1021/ol202548q
Published on Web 11/09/2011
2011 American Chemical Society

slows the overall rate. Thus, if the ligand could be effi-
ciently scavenged, faster reactions would occur. Most
scavenging strategies involve chemical trapping.6 How-
ever, phase transfer into an orthogonal solvent represents
another possibility. Toward this end, a biased partition
coefficient is also required.
Scheme 2. Water-Soluble Phosphines and Ruthenium Com-
plexes Thereof Used in This Study
Extensive studies have established the initial steps de-
picted in Scheme 1 (bottom) for the mechanism of Grubbs’
first and second generation metathesis catalysts.7 In a pre-
vious study, we showed that significant rate accelerations
occurred when analogs of Grubbs’ second generation
catalyst with fluorous phosphines P((CH2)mRfn)3 (Rfn
=
(CF2)nꢀ1CF3) were conducted under organic/fluorous bi-
phasic conditions as opposed to organic monophasic con-
ditions (Scheme 1, right vs left).8 This was attributed to
rapid transfer of the dissociated phosphine to the fluorous
phase, which effectively eliminated competition of non-
productive phosphine reassociation (k step, Scheme 1)
ꢀ1
with productive alkene binding (k2 step).
Scheme 1. Phase Transfer Activation of Analogs of Grubbs’
Second Generation Alkene Metathesis Catalyst with Fluorous
Phosphines under Organic/Fluorous Liquid/Liquid Biphase
Conditions
series were investigated. The first featured a triphenylpho-
sphine core in which one or three phenyl groups were
functionalized by a sodium sulfonate moiety in a meta
position (TPPMS, TPPTS; 2a,b). This provides steadily
increasing hydrophilicity. The second featured trialkyl
phosphines containing one or two tetraalkylammonium
halide groups (2cꢀe).
As shown in Scheme 2 (middle), the ruthenium bis-
(pyridine) benzylidene complex (H2IMes)(Py)2(Cl)2Ru-
(dCHPh) (3; H2IMes=1,3-dimesityl-4,5-dihydroimida-
zol-2-ylidene)11 and the phosphines were combined under
homogeneous conditions in the polar solvent methanol.
NMR analyses of the reaction with 2a showed only 10%
conversion to a new benzylidene complex, and no con-
version was observed with 2b. However, workups of
the reactions with 2cꢀe gave the new complexes 4cꢀe
(Scheme 2, bottom) as analytically pure brownish
solids in 85ꢀ65% yields.
Since we were unaware of any additional examples of
such “phase transfer activation” of catalysts in the litera-
ture, further validation of the concept was sought. Accord-
ingly, in this communication we extend Scheme 1 to
aqueous/organicbiphasesystemsusinganalogsofGrubbs’
second generation catalyst with water-soluble phosphines.
Furthermore, we find that even more pronounced rate
accelerations occur when aqueous HCl is employed as the
orthogonal phase, presumably due to protonation of the
dissociated ligand.9
The phosphines depicted in Scheme 2 (top) were pur-
chased or synthesized by literature procedures.10 Two
The new complexes were characterized by NMR spec-
troscopy (1H, 13C, 31P), as summarized in the Supporting
1
Information (SI). All features were routine, with the H
(6) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324.
(7) (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543. (b) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs,
R. H. J. Am. Chem. Soc. 2003, 125, 10103.
and 13C NMR data sharing many features with those of
Grubbs’ second generation catalyst. Since CH2Cl2 is a
common solvent for alkene metathesis, H2O/CH2Cl2 par-
tition coefficients for the complexes and phosphine ligands
were determined as described in the experimental section
(SI) and summarized in Table 1. Surprisingly, there appear
to be little quantitative data on the relative aqueous/organic
^
(8) (a) Correa da Costa, R.; Gladysz, J. A. Chem. Commun. 2006,
^
2619. (b) Correa da Costa, R.; Gladysz, J. A. Adv. Synth. Catal. 2007,
349, 243.
(9) For Brønsted basicities of phosphines, see the following recent
articles and earlier references therein: (a) Streitwieser, A.; McKeown,
A. E.; Hasanayn, F.; Davis, N. R. Org. Lett. 2005, 7, 1259. (b) Pestovsky,
O.; Shuff, A.; Bakac, A. Organometallics 2006, 25, 2894.
(10) Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996, 15,
4317.
(11) Sanford, M. S.; Love, J. A.; Grubbs, R. H. Organometallics
2001, 20, 5314.
Org. Lett., Vol. 13, No. 23, 2011
6189

Table 1. Partition Coefficients (H2O/CH2Cl2, 24 °C) for Water-
Soluble Phosphines and Their Corresponding Grubbs’
Catalysts
Scheme 3. Phase Transfer Activation of Analogs of Grubbs’
Second Generation Alkene Metathesis Catalyst with Water-
Soluble Phosphines under Organic/Aqueous Liquid/Liquid
Biphase Conditions
partition
ruthenium
complex
partition
phosphine
coefficient
coefficient
2a
2b
2c
>99.9:<0.1
>99.9:<0.1
92.8:7.2
(>99.9:<0.1)a
--
--
--
--
4c
<0.1:>99.9
2d
2e
80.7:19.3
4d
4e
<0.1:>99.9
>99.9:<0.1
(>99.9:<0.1)a
>99.9:<0.1
a 0.10 M aqueous HCl used in place of H2O; analysis after addition of
base.
solubilities of hydrophilic phosphines in the literature. In
accord with the coloration of the biphasic mixtures, the
monotetraalkylammonium salts 4c,d partitioned exclusively
into the organic phase, and the bis(tetralkylammonium) salt
4e exclusively into the aqueous phase.
The data in Table 1 help to identify the most promising
catalyst systems for aqueous/organic phase transfer acti-
vation of alkene metathesis. Complex 4e is too hydrophilic
and will be orthogonal to the reactant phase. With the
lipophilic complexes 4c,d, both phosphine ligands prefer-
entially partition into the aqueous phase, but that in 4c to a
somewhat greater extent.
Substrates that would react at convenient time scales
between room temperature and 0 °C were sought, and
based upon screening experiments the reactions depicted
in Scheme 3 were selected. The ring closing metathesis of
N-allyl-N-methallyltosylamide (5) to 6 was conducted using
2.0 mL of a 0.050 M CH2Cl2 solution and 2.5 mol % of 4c.
The rate of conversion of 5 was monitored by GC with
reference to a tridecane internal standard. Data are sum-
marized in Figure 2. Then an otherwise identical reaction
was conducted in the presence of water (1.0 mL), corre-
sponding to B in Scheme 3 (bottom). As shown in Figure 2,
a significant rate acceleration was observed.
Next, an otherwise identical reaction was conducted in
the presence of 1.0 M aqueous HCl (1.0 mL; C in Scheme 3).
Now a more dramatic rate acceleration was observed. This
is consistent with protonation of the phosphine ligand 2c
following phase transfer,9 and the much more biased
partition coefficient that results (Table 1). Grubbs has also
observed faster metatheses in the presence of HCl in
systems that do not involve phase transfer.3b,12
In another series of experiments (SI), the concentration of
HCl in the aqueous phase was varied. Comparable rate data
were obtained with 1.0, 0.10, and 0.010 M aqueous HCl
(Figure s1). Hence, the latter was used in subsequent
experiments below. Also, when the catalyst loading in the
H2O/CH2Cl2 experiment was decreased to 1.0 mol %, there
was a corresponding decrease in rate. However, the rate was
Figure 2. Rates of formation of 6 (room temperature, [5]0 =
0.049ꢀ0.050 M, 2.5 mol % 4c). Solvent systems: A (blue,[)
CH2Cl2 (2.0 mL); B (red,9) CH2Cl2/H2O (2.0 mL/1.0 mL); C
(gold,2) CH2Cl2/1.0 M aqueous HCl (2.0 mL/1.0 mL).
essentially unchanged when the catalyst loading was in-
creased to 5.0 mol % (Figure s2).
The generality of these phenomena was tested with other
catalysts and substrates. Figure 3 depicts a series of
experiments similar to those in Figure 2, but using com-
plex 4d. This catalyst was intrinsically more active, so the
(12) Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153.
6190
Org. Lett., Vol. 13, No. 23, 2011

under otherwise identical conditions, but in the presence
of the fluorous solvent perfluoro(2-butyltetrahydrofuran)
(FC-75;1.0 mL). Aslightratedecreasewasnoted(Figures3).
Finally, when Grubbs’ second generation catalyst was em-
ployed in place of 4c in Figure 2 (monophasic conditions), a
Figure 3. Rates of formation of 6 (0 °C, [5]0 = 0.050ꢀ0.051 M,
1.0 mol % 4d). Solvent systems: A (blue,[) CH2Cl2 (4.0 mL); B
(red,9) CH2Cl2/H2O (4.0 mL/2.0 mL); C (gold,2) CH2Cl2/0.010
M aqueous HCl (4.0 mL/2.0 mL).
metathesis was conducted at 0 °C with a 1.0 mol %
loading. Parallel effects were observed, although the mag-
nitudes of the rate accelerations were less, possibly due in
part to the less biased partition coefficient of the dissociat-
ing phosphine 2d.
Figure 5. Rates of formation of 10 (0°C, [9]0 = 0.050 M, 1.0 mol %
4c). Solvent systems: A (blue,[) CH2Cl2 (4.0 mL); B (red,9)
CH2Cl2/H2O (4.0 mL/2.0 mL); C (gold,2) CH2Cl2/0.010 M aqu-
eous HCl (4.0 mL/2.0 mL).
Next, a series of experiments comparable to those in
Figure 2 was conducted with catalyst4c and diethyl 2-allyl-
much faster reaction occurred. Hence, 4c and 4d are intrinsi-
cally less active metathesis catalysts.
In summary, we have established that the new catalysts
4c and 4d can effect a variety of ring closing metatheses and
that these reactions are significantly accelerated when
conducted in the presence of water or aqueous HCl. These
data are consistent with a phenomenon that can be termed
“phase transfer activation”, whereby the hydrophilic phos-
phine ligand is rapidly transferred to the aqueous phase,
diminishing competition from the nonproductive kꢀ1 step
in the mechanism sketched in Scheme 1. In the case of
aqueous HCl, the phosphine ligand is furthermore proto-
nated, which further decreases the equilibrium concentration
of the phosphine in the reaction phase and may kinetically
assist crossing the phase boundary. There are a number of
attractive possibilities for extending this concept,13 and
additional examples will be reported in due course.
Figure 4. Rates of formation of 8 (room temperature, [7]0 =
0.050 M, 2.5 mol % 4c). Solvent systems: A (blue,[) CH2Cl2
(2.0 mL); B (red,9) CH2Cl2/H2O (2.0 mL/1.0 mL); C (gold,2)
CH2Cl2/0.010 M aqueous HCl (2.0 mL/1.0 mL).
Acknowledgment. We thank the Qatar National Research
Fund for support (Project No. 08-607-1-108).
2-methallylmalonate (7; Scheme 3). As shown in Figure 4,
analogous rate accelerations were realized under biphasic
conditions, with aqueous HCl being more effective
than water alone. Similar results were obtained with the
N-tosylamide 9 (Scheme 3), which affords the six-mem-
bered heterocycle 10, as summarized in Figure 5.
Supporting Information Available. Details of the synth-
esis and characterization of 4cꢀe, catalysis experiments, and
partition coefficient measurements. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(13) For example, analogs of Grubbs’ second generation catalyst
have been prepared with imidazolium containing phosphine ligands,
which impart high affinities for imidazole based ionic liquids: Consorti,
C. S.; Aydos, G. L. P.; Ebeling, G.; Dupont, J. Org. Lett. 2008, 10, 237.
As a control experiment, the reaction conducted in
CH2Cl2 in Figure 2 was compared with one conducted
Org. Lett., Vol. 13, No. 23, 2011
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