Studies of a soluble polyethylene glycol immobilized ruthenium catalyst in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2010.12.046

We have developed an air-stable soluble polyethylene glycol bound ruthenium catalyst which performs efficient ring-closing metathesis in organic solvents as well as in aqueous media.

Full text of DOI:10.1016/j.tetlet.2010.12.046

Tetrahedron Letters 52 (2011) 878–880
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies of a soluble polyethylene glycol immobilized ruthenium catalyst
in aqueous media
Shazia Zaman a, , Hongyuan Chen a, Andrew D. Abell b,
⇑
⇑
a Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch, New Zealand
b School of Chemistry and Physics, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an air-stable soluble polyethylene glycol bound ruthenium catalyst which performs
efficient ring-closing metathesis in organic solvents as well as in aqueous media.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 August 2010
Revised 30 November 2010
Accepted 10 December 2010
Available online 17 December 2010
Well-defined ruthenium-based catalysts such as 1a and 1b are
widely used in a range of organic solvent-based olefin metathesis
reactions because of their high functional group tolerance and ease
of handling. While these catalysts do show some stability and
activity in the presence of water,1 their use in aqueous media is
limited by a lack of solubility.2 Various approaches have been
developed to begin to overcome this shortcoming.3
We recently reported 8 as a soluble polyethylene glycol (PEG)
immobilized catalyst with good activity in RCM of various bench-
mark substrates in dichloromethane in air, and with the ability
to be recycled up to five times without significant loss of activity.14
As part of our programme to develop aqueous active catalysts, we
now report the results of using this catalyst to promote aqueous-
based ring-closing metathesis (RCM) reactions of N,N-diethyldiallyl
A number of water-soluble catalysts have been reported that
contain a water-solubilising ligand, for example, as in 2a and
2b.4 These catalysts successfully promote ring-opening metathesis
polymerization (ROMP) in aqueous media5 and show limited ring-
Me
Me
Cl
N
R
Ru
Ph
closing metathesis (RCM) activity of simple
a,x-dienes in metha-
Cl
Cl
NMe3 Cl
Ph
nol.6 An improved catalyst 3 with a heterogeneous hydrophilic
polymeric support, PEGA attached to the benzylidene ligand has
been reported.7 This catalyst successfully performs various RCM
and cross metathesis (CM) reactions in methanol and water.7 The
hydrophilic polyethylene glycol supported NHC carbene 4 also
shows good aqueous ROMP activity in water, however, its pendant
PEG-carbamoyl-benzyl group limits the stability of the intermedi-
ate ruthenium alkylidene.8 Catalyst 5, with a PEG-soluble support
appended to the NHC ligand, is reported to form aggregates in
water with improved ROMP, RCM and CM activity of water-soluble
substrates.9 Other recently reported catalysts that are active in
aqueous mixtures and neat water include 6 and 7.10 In these cases
a quaternary ammonium salt is attached to the benzylidene ligand
to improve aqueous solubility (Fig. 1). More recently, micellar
catalysis has also been used for aqueous metathesis. Water emul-
sions can be stabilized by various amphiphiles11 or supramolecular
additives.12 Another approach to overcome the low solubility of
the catalyst in water is to use mixed water-organic solvent reaction
media.13
P
Ru
PCy2
Ru
PCy2
Ph
H
Cl
Cl
PCy3
Cl
Cl
H
1a
1b
, R = PCy3
P
NMe3 Cl
Mes
N
, R =
Cl
N
N
Me
Me
Mes
2a
2b
NMes
MesN
Cl
O
Ru
MePEGO
Cl
N
O
H
NMes
Ru
N
N
Cl
Cl
O
OPEGMe
3
Ph
PCy3
PEGA
NMes
MesN NMes
4
Cl
MesN
Cl
Ru
Cl
Ru
O
Cl
O
5
NMes
N+MeEt2I-
NMes
MesN
6
Cl
Cl
Ru
O
MesN
Cl
Cl
Cl
Ru
O
N
Me
NMe3
Cl
7
Me
OPEGMe
⇑
Corresponding authors. Tel.: +61 8 8303 5652; fax: +61 8 8303 4358 (A.D.A.).
E-mail addresses: shaziazaman_99@yahoo.com (S. Zaman), andrew.abell@
8
adelaide.edu.au (A.D. Abell).
Figure 1. Ruthenium-based catalysts for olefin metathesis in aqueous media.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.046

S. Zaman et al. / Tetrahedron Letters 52 (2011) 878–880
879
Table 1
Studies of catalyst 8 in different aqueous systems in the RCM of diene 916
Table 2
Ring-closing metathesis of various substrates using catalyst 8
Entry
Substrateref
Product
Conversiona (%)
EtO2C CO2Et
EtO2C CO2Et
8 (5 mol%)
RT, solvent
A
B
Tsb
N
Ts
N
915
1015
1
2
98
98
98
Entry
1
Solvent
Time (h)
Conversiona (%)
1217
1117
EtOH/H2Ob
1
16
1
16
1
57
72
42
50
73
95
Ts
Ts
N
N
2
3
MeOH/H2Ob
Me2CO/H2Ob
98
98
1317
1417
16
Ts
Ts
Determined by analysis of the 1H NMR spectrum of the crude product.
2:1, v/v.
a
N
N
b
3
4
95
72
1517
1617
malonate (9) (a metathesis benchmark substrate)15 and a range of
other dienes.
Ts
Ts
N
N
In the first instance, RCM of 9 was investigated under three sep-
arate aqueous conditions in order to establish optimum conditions
and catalyst efficiency (see Table 1). The diene 9 was treated with
5 mol % of catalyst 8 at RT in the specified solvent system, with
conversion into 10 being monitored after both 1 and 16 h by 1H
NMR spectroscopy.
83
71
1717
1818
Ts
Ts
N
N
5
6
52
90
1917
The results in Table 1 reveal that acetone/water (2:1, v/v) was
the optimum solvent system for RCM, with a 95% conversion of 9
into 10 after 16 h. This can be compared to ethanol/water and
methanol/water systems that resulted in 72% and 50% conversion,
respectively. Thus subsequent reactions, as shown in Table 2, were
carried out using this acetone/water (2:1, v/v) solvent system.16
The efficacy of catalyst 8 was next tested in the ring-closing
metathesis reactions of a series of di- and tri-substituted N-tosyl
based-dienes (11, 13, 15, 17 and 19), b-amino acid derived dienes
(21 and 23) and the water-soluble ammonium chloride based
diene 25. Again the extent of cyclisation (to give 12, 14, 16, 18,
20, 24 and 26) was determined by 1H NMR spectroscopy after both
1 and 16 h reaction times (Table 2). The reactions were run at a
concentration of 0.2 M and no attempt was made to exclude air.
Catalyst 8 is particularly efficient at forming both five- and six-
membered N-containing heterocycles. For example, the N-tosyl-
diallyl dienes 11, 13 and 15 all gave near quantitative conversion
to the heterocycle after 1 h (see entries 1–3 in Table 2). Interest-
ingly, diene 17 which contains a trisubstituted alkene, cyclised less
efficiently with a 72% conversion after 1 h and a slightly improved
83% yield after 16 h (entry 4, Table 2). It is apparent that a seven-
membered heterocycle is formed less efficiently, with only 52%
cyclisation of diene 19 into 20 after 1 h. This only increased to
71% after the extended 16 h reaction time. It appears that introduc-
ing further substitution (not on the alkene) to the acyclic precursor
diene, as in 21,19,20 significantly enhances conversion into the het-
erocycle, with 90% conversion into 2221 after only 1 h reaction. This
observation is consistent with the well-known Thorpe–Ingold22 ef-
fect. The diene 2323 lacking an amine cyclised less efficiently to
give the five-membered ring product 2423 in only a 67% yield after
1 h (see entry 7 in Table 2). Finally, the ability of catalyst 8 to cata-
lyse RCM in water was determined using the water-soluble diene
substrate 25. Significantly, 35% conversion into the five-membered
heterocycle 26 was observed after an extended 16 h reaction time
(Table 2, entry 8). RCM of diene 25 in the presence of catalysts 59
and 710 in neat water, however, resulted in the formation of a
by-product along with 26 due to cycloisomerisation which was
not observed in the presence of 8.
2015
Cbz
Cbz
N
N
MeO2C
98
MeO2C
BocHN
2221
2119
CO2Me
CO2Me
BocHN
7
8
67
<5
72
35
2323
2423
H2Cl
N
H2Cl
N
25
26
Determined by analysis of the crude 1H NMR spectrum.
p-Toluene sulfonamide A:1 h; B; 16 h.
a
b
can be conveniently prepared by the reaction of Grubbs’ second
generation catalyst with PEG-bound olefin.14
Acknowledgements
Financial support from the Royal Society of New Zealand Mars-
den fund and the Australian Research Council (ARC) is gratefully
acknowledged. The authors thank Professor Robert Grubbs at the
California Institute of Technology and Dr. Axel Neffe at the Institute
of Polymer Research Centre GKSS Forschungszentrum GmbH, Tel-
tow, Germany for useful suggestions. S.Z. would like to thank Dr.
Emily Parker (University of Canterbury) for her support.
References and notes
1. (a) Grubbs, R. H.; Trnka, T. M.; Sanford, M. S. Curr. Methods Inorg. Chem. 2003, 3,
187–231; (b) Bielawski, C. W.; Benitez, D.; Grubbs, R. H. Science 2002, 297,
2041–2044; (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
2. Lynn, D. M.; Kanaoka, S.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 784–790.
3. Zaman, S.; Curnow, O. J.; Abell, A. D. Aust. J. Chem. 2009, 62, 91–100.
4. Bernhard, M.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996, 15, 4317–4325.
5. Lynn, D. M.; Mohr, B.; Grubbs, R. H. J. Am. Chem. Soc. 1998, 120, 1627–1628.
6. Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 9904–9909.
In summary, these findings demonstrate that the polyethylene
glycol supported ruthenium catalyst 8 exhibits good RCM activity
in acetone/water (2:1, v/v) in the presence of air. The catalyst

880
S. Zaman et al. / Tetrahedron Letters 52 (2011) 878–880
7. Connon, S. J.; Blechert, S. Bioorg. Med. Chem. Lett. 2002, 12, 1873–1876.
8. Gallivant, J. P.; Jordan, J. P.; Grubbs, R. H. Tetrahedron Lett. 2005, 46, 2577–2580.
(1.83 ml, 2.59 mmol) was added, and the mixture stirred at À78 °C for 1 h and
then allyl bromide (219
L, 2.59 mmol) was added. This was stirred at À78 °C
l
9. Hong, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 3508–3509.
10. Jordan, J. P.; Grubbs, R. H. Angew. Chem., Int. Ed. 2007, 46, 5152–5155.
11. (a) Lipshutz, B. H.; Ghorai, S.; Aguinaldo, G. T. Adv. Synth. Catal. 2008, 350, 953–
956; (b) Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K. Org. Lett.
2008, 10, 1325–1328.
12. Brendgen, T.; Fahlbusch, T.; Frank, M.; Schühle, D. T.; Seßler, M.; Schatz, J. Adv.
Synth. Catal. 2009, 351, 303–307.
13. Binder, J. B.; Blank, J. J.; Raines, R. T. Org. Lett. 2007, 9, 4885–4888.
14. Zaman, S.; Abell, A. D. Tetrahedron Lett. 2009, 50, 5340–5343.
15. Yao, Q. J. Am. Chem. Soc. 2004, 126, 74–75.
16. In a typical experiment, catalyst 8 (0.05 equiv) was added to a 1 ml vial,
equipped with a magnetic stir-bar and sealed with a septa-cap. The vial was
then charged with a 0.2 M solution of diene in acetone/H2O (2:1, v/v). The
reaction was stirred at room temperature without exclusion of air. The
progress of the reaction was analysed by 1H NMR after 1 h and overnight for all
the reactions studied.
17. Terada, Y.; Mitsuhiro, M.; Nishida, A. Angew. Chem. 2004, 116, 4155–4157.
Angew. Chem., Int. Ed. 2004, 43, 4063–4067.
18. Tamaru, Y.; Hojo, M.; Yoshida, Z.-I. J. Org. Chem. 1988, 53, 5731–5741.
for a further 2 h and then at rt for 18 h. The mixture was concentrated in vacuo
and the residue partitioned between EtOAc (40 ml) and 1 M HCl (aq, 20 ml).
The organic phase was washed consecutively with 1 M HCl (aq, 20 ml) and
brine (30 ml) and then dried over MgSO4, filtered and concentrated in vacuo.
The crude material was purified by flash chromatography on silica using EtOAc
and petroleum ether (30:70) to give 21 as a mixture of rotamers (0.335 g, 81%)
as a colourless oil. 1H NMR (CDCl3, 500 MHz), d 7.18–7.28 (m, 5H), 5.53–5.67
(m, 2H), 4.90–5.18 (m, 6H), 3.87–3.95 (m, 1H), 3.61–3.70 (m, 1H), 3.53–3.59
(m, 3H), 3.30–3.45 (m, 2H), 2.73–2.85 (m, 1H), 2.09–2.27 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d 174.93, 174.76, 156.40, 156.24, 136.91, 136.71, 134.79,
134.68, 133.74, 133.52, 128.69, 128.57, 128.36, 128.22, 127.97, 117.48, 116.85,
67.63, 67.39, 51.95, 51.93, 50.78, 49.31, 48.14, 44.89, 44.42, 34.56; [MH]+
requires: 318.1661, observed: 318.5803.
20. Podlech, J.; Seebach, D. Liebigs Ann. Chem. 1995, 1217.
21. The diene 21 (31 mg) and catalyst
8 (13 mg) in acetone/H2O (2:1,
330 l:165 ll) were stirred at room temperature giving 22 as a mixture of
l
rotamers as a colourless oil. Data for the mixture: 1H NMR (CDCl3, 500 MHz) d
H 7.29–7.36 (m, 5H), 5.62–5.79 (m, 2H), 5.09–5.19 (m, 2H), 4.17–4.26 (m, 1H),
3.84–4.18 (m, 1H), 3.61–3.74 (m, 4H), 2.91–2.98 (m, 1H), 2.44–2.48 (m, 2H);
[MH]+ requires: 290.1392, observed: 290.1404.
19. (S)-Methyl
2-[{(allyl(benzyloxycarbonyl)amino}methyl]pent-4-enoate
(21):
Arndt–Eistert homologation20 of N-Cbz-(S)-glycine followed by stereo-
controlled allylation gave (S)-methyl 2-[{(benzyloxycarbonyl)amino}methyl]-
pent-4-enoate (27). A solution of 27 (360 mg, 1.29 mmol) was dissolved in
anhydrous THF (30 ml). This was cooled to À78 °C and P4-phosphazene
22. For a review on the Thorpe–Ingold effect, see: Jung, M. E.; Piizzi, G. Chem. Rev.
2005, 105, 1735–1766.
23. Gardiner, J.; Anderson, K. H.; Downard, A.; Abell, A. D. J. Org. Chem. 2004, 69,
3375–3382.