Olefin cross-metathesis reactions at room temperature using the nonionic amphiphile "PTS": Just add water

Article abstract of DOI:10.1021/ol800028x

(Chemical Equation Presented) The first examples of unsymmetrical olefin cross-metathesis reactions in water, involving water-insoluble substrates, at room temperature and using commercially available catalysts are reported. The key to success is to include small percentages of the nonionic, vitamin E-based amphiphile "PTS". The nanometer micelles formed accommodate water-insoluble substrates, along with a readily available Ru-based metathesis catalyst. Reactions proceed at ambient temperatures with high efficiency and very high E-selectivity, and products are easily isolated.

Full text of DOI:10.1021/ol800028x

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1325-1328
Olefin Cross-Metathesis Reactions at
Room Temperature Using the Nonionic
Amphiphile “PTS”: Just Add Water†
Bruce H. Lipshutz,* Grant T. Aguinaldo, Subir Ghorai, and Karl Voigtritter
Department of Chemistry & Biochemistry, UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received January 6, 2008
ABSTRACT
The first examples of unsymmetrical olefin cross-metathesis reactions in water, involving water-insoluble substrates, at room temperature and
using commercially available catalysts are reported. The key to success is to include small percentages of the nonionic, vitamin E-based
amphiphile “PTS”. The nanometer micelles formed accommodate water-insoluble substrates, along with a readily available Ru-based metathesis
catalyst. Reactions proceed at ambient temperatures with high efficiency and very high E-selectivity, and products are easily isolated.
Reactions run in water offer several advantages: safety,
economics, environmental compatibility, etc.1 Nonetheless,
there are also drawbacks, not the least of which is the limited
aqueous solubility of most neutral organic substrates. In the
specific case of olefin metathesis chemistry2 also involving
a water-insoluble (ruthenium-based) catalyst, these issues can
present serious limitations. Partial solutions have been
forthcoming,3 where tetraalkylammonium phosphines,4 sul-
fonated phosphines,5 PEGylated NHC ligands,6 or
pendant tetralkylammonium7 residues adorning the ruthenium
carbene have been reported. Although these approaches lead
to water-soluble catalysts, a sequence of steps is required in
each preparation. Moreover, the solubility profile of the
olefinic partners remains unaddressed. Particularly challeng-
ing are the cases involving intermolecular cross-metathesis
(CM)2e,8 of unsymmetrical lipophilic alkenes in water, for
which no known technology currently exists. We now
describe an especially simple protocol for effecting olefin
CM at room temperature, in water, in the absence of
cosolvents and without recourse to alterations in substrate
or commercial catalyst design.
† Dedicated with greatest respect and admiration to Professor E. J. Corey,
Nobel Laureate, on the occasion of his 80th birthday.
(1) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie: London,
1998. (b) Lindstrom, U. M. Chem. ReV. 2002, 102, 2751-2772. (c) Aqueous-
Phase Organometallic Catalysis: Concepts and Applications, 2nd ed.;
Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: Weinheim, 2004. (d)
Organic Reactions in Water; Lindstrom, U. M., Eds.; Blackwell Publishing
Ltd.: Oxford, 2007.
Screening of several amphiphiles 1-6 (Figure 1) in the
CM between allylbenzene and tert-butyl acrylate (2 equiv)
(2) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (c) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (d) Schrock, R. R.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592-4633. (e) Connon,
S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900-1923. (f)
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003.
(g) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238. (h)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4490-4527. (i) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed.
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2007, 40, 45-52.
(4) (a) Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996,
15, 4317-4325. (b) Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org.
Chem. 1998, 63, 9904-9909. (c) Lynn, D. M.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 3187-3193.
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3509.
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Kirschning, A.; Grela, K. Green Chem. 2006, 8, 685-688. (b) Jordan, J.
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10.1021/ol800028x CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/12/2008

Table 1. Comparison of Amphiphiles for CM in Water
entry
surfactanta
yieldb,c (%)
yieldc,d (%)
1
2
3
4
5
6
7
8
PTS
TPGS
PSS
Triton X-100
Brij 30
PEG-600
SDS
1
2
3
4
5
97
67
78
69
63
60
68
71
93
61
70
63
55
47
64
62
6
none
a 2.5% used in all cases. b Using 2 equiv of acrylate. c Isolated yields of
chromatographically pure materials. d Using 1.3 equiv of acrylate.
Figure 1. Structures of surfactants screened.
with continuous stirring overnight afforded the desired enoate
11 in high isolated yield. Switching from 7b to the first-
generation Grubbs complex 7a12 under otherwise identical
conditions led to mainly recovered educts, along with both
cis- and trans-isomers of the homocoupled unactivated
alkene, and <2% of the butenoate, indicative of the
importance of catalyst selection.
using the Grubbs-2 catalyst 7b9 (2 mol %; Figure 2), among
several possible candidates,10 indicated that the PEG-600/
Other nonionic surfactants, including the structurally close
yet less lipophilic analog TPGS (2),13 produced more
homocoupling products, and hence, lower yields of 11 (Table
1, entry 2). Replacing the vitamin E subsection of PTS with
â-Sitosterol, thereby forming the equally lipophilic “PSS”
(3),11 did not give competitive results (entry 3). Other neutral
carriers such as Triton X-100 (4)14a and Brij 30 (5)14b afforded
no improvement (entries 4 and 5, respectively). Neither PEG-
60014c alone (entry 6) nor the common ionic surfactant
sodium dodecyl sulfate (SDS) (6)14d afforded yields (entry
7) that were any higher than that from the control reaction
performed “on water” (entry 8).15
The combination of 2% Grubbs-2 catalyst in 2.5% PTS/
water forms a stable, rose-colored colloidal dispersion (Figure
3A). Although upon standing at room temperature for days
Figure 2. Structures of common Ru-based catalysts used for olefin
metathesis.
R-Tocopherol-based diester of Sebacic acid, PTS (1; MW
∼1200),11 is the most effective (Table 1, entry 1). Adding a
preformed, essentially water-white solution of only 2.5% (by
weight) PTS in water to a 2:1 mixture of olefins and catalyst
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
Figure 3. Appearance of Grubbs-2 catalyst in (A) 2.5% (w/w)
PTS/water and (B) neat water.
(10) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonetatebus, P. J., Jr.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791-799. (b) Garber, S. B.;
Kingsbury, J. S.; Grey, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168-8179. (c) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett.
2000, 41, 9973-9976. (d) Grela, K.; Haruyunyan, S.; Michrowska, A.
Angew. Chem., Int. Ed. 2002, 41, 4038-4040. (e) Michrowska, A.; Bujok,
R.; Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem.
Soc. 2004, 126, 9318-9325. (f) Wakamatsu, H.; Blechert, S. Angew. Chem.,
Int. Ed. 2002, 41, 2403-2405. (g) Deshmukh, P. H.; Blechert, S. Dalton
Trans. 2007, 2479-2491.
the catalyst will begin to precipitate, stirring briefly restores
the mixture to its original state. In the presence of reactants,
the solution darkens while the CM product forms over a few
hours time. Without PTS, there is no dissolution (Figure 3B).
1326
Org. Lett., Vol. 10, No. 7, 2008

As the many successful examples in Table 2 indicate, these
conditions are quite general. Particularly noteworthy features
of the process include the following; (1) its simplicity; while
most CM reactions are done at higher temperatures (40
°C)8,16,17 these reactions are conducted at room temperature
open in air;10g (2) E/Z ratios tend to be comparable to those
typically observed in organic media;8,16,17 (3) many functional
groups are tolerated, such as allylic silanes, free alcohols,
amino acid derivatives, and epoxides; (4) highly lipophilic
partners smoothly participate; (5) product isolation is straight-
forward.18 Unpredictably, the extent of homocoupling is
oftentimes improved in aqueous PTS, suggesting the potential
for lowering of the ratio of olefinic partners toward 1:1.19
In fact, at a ratio of 1.3:1 there is minimal loss for the model
case studied (Table 1, second column of yields), while the
corresponding yields with other surfactants (or in water
alone) dropped due to increased competing homocoupling.
Problematic substrates included more hindered cases such
as methyl methacrylate and acrylonitrile (low conversion).10e,20
A sequence involving allylbenzene (12) and a symmetrical
1,2-disubstituted olefin such as diacetate 13 worked well,
affording 14 (Scheme 1, eq 1).8 Likewise, initial ring-opening
Table 2. Olefin CM Reactions Using 2% Catalyst in 2.5% aq
PTSa
Scheme 1. Other Examples of CM in PTS/water
reactions that subsequently converted cyclohexene (with tert-
butyl acrylate) to all-E diester 15,16 and with methyl vinyl
ketone (MVK) to diketone 16, were successful (Scheme 1,
eq 2).21
The success of PTS, an amphiphile that itself forms on
average 22 nm micelles in water above its critical micelle
(11) (a) Borowy-Borowski, H.; Sikorska-Walker, M.; Walker, P. R.
Water-Soluble Compositions of Bioactive Lipophilic Compounds. U.S.
Patent 6,045,826, Apr 4, 2000. (b) Borowy-Borowski, H.; Sikorska-Walker,
M.; Walker, P. R. Water-Soluble Compositions of Bioactive Lipophilic
Compounds. U.S. Patent 6,191,172, Feb 20, 2001. (c) Borowy-Borowski,
H.; Sikorska-Walker, M.; Walker, P. R. Water-Soluble Compositions of
Bioactive Lipophilic Compounds. U.S. Patent 6,632,443, Oct 14, 2003.
(12) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1995, 34, 2039-2041. (b) Schwab, P.; Grubbs, R. H.; Ziller,
J. W. J. Am. Chem. Soc. 1996, 118, 100-110.
(13) PCI-102B Eastman Vitamin E TPGS NF - Applications and
Properties. http://www.eastman.com/NR/rdonlyres/A2FE037B-0778-4A90-
A0FC-5D07BE51064A/0/PCI102.pdf (accessed August 2007).
(14) Sigma-Aldrich catalog nos. (a) 234729, (b) P4391, (c) 202401, (d)
L3771.
(15) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolib, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275-3279. See also:
Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem.,
Int. Ed. 2007, 46, 3798-3800.
a Reactions were conducted at 0.5 M over 12 h at 22 °C using Grubbs-2
(7b). b Isolated yield of chromatographically pure materials. c E/Z ratio
determined by 1H NMR. d Using Grubbs-Hoveyda-2 (8b). e Based on
recovered starting material. f Isolated. g Isolated as an inseparable mixture
with styrene homocoupling product (8%); ratio determined by 1H NMR.
Org. Lett., Vol. 10, No. 7, 2008
1327

concentration (0.28 mg/g),22 may be related to its hydrophilic
lipophilic balance (HLB).23 That is, on the commonly used
(albeit arbitrary) scale of 0-20 (Figure 4), PTS (HLB )
the factors controlling the interior nature of these micelles,
and their abilities to “host” organometallic reactions of
interest to synthetic chemists.24
In summary, a nonionic surfactant has been identified that
leads to a new, general protocol for effecting olefin metathe-
sis in water at ambient temperatures. Intermolecular cross-
couplings can be carried out in high yields and with
E-selectivities comparable to those expected in organic
media. Reactions take place under very mild and “green”
conditions. No modifications of catalyst or substrate are
required to enhance their water solubility, nor are there any
special techniques or handling procedures of the materials
involved.25 Further successful applications to several other
“name” reactions (e.g., Sonogashira couplings), in addition
to the two which follow in this issue will be reported in due
course.26
Figure 4. Hydrophilic lipophilic balance scale.
Acknowledgment. Financial support provided by Zymes,
LLC is warmly acknowledged with thanks. Catalysts were
generously provided by Materia, Inc. (J. Kibler and R.
Pederson), for which we are most grateful. TPGS was
generously provided by Eastman.
10) is less hydrophilic relative to most other common
nonionic carriers. This position reflects its higher percentage
of hydrocarbon (due to vitamin E + the 10-carbon sebacic
acid linker) and lower content of PEG (involving only PEG-
600). The HLB, however, is merely a relative index which
ignores entirely the specific makeup of the amphiphile’s
components. Thus, based on this scale, Brij20 30 (5) has an
HLB similar to that of PTS. However, the lipophilic portion
of its 5-6 nm micelles formed in water22 appears not to
provide the most appropriate environment for this catalysis.
These observations are in line with data on Pd-catalyzed
processes in PTS/water, including Heck22a and Suzuki-
Miyaura22b coupling. The key role of the R-tocopheryl
subsection in 1 is further supported by direct comparison
with equally lipophilic PSS (3), which self-aggregates into
similarly sized micelles (ca. 20 nm) in water and has
essentially an identical HLB. Nonetheless, results with this
carrier for olefin CM are inferior to those realized using PTS.
These data suggest that there is much yet to be learned about
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800028X
(24) Since PEG-600 is supplied as a mixture of compounds, so therefore,
PTS is a mixture of PEG monoesters, the distribution of which is readily
observed by mass spectrometry. Moreover, while synthesis of PTS is
straightforward (i.e., from sebacoyl chloride, racemic vitamin E, and PEG-
600),11 a complete understanding of the roles of its various ingredients,
including impurities (e.g., PEG diesters, etc.) in micelle formation remains
to be elucidated.
(25) Representative procedure for olefin CM (Table 2, entry 8): 10-
Undecenol (94.8 mg, 0.556 mmol), tert-butyl acrylate (159.5 mg, 1.24
mmol), and Grubbs second-generation catalyst 7b (9.9 mg, 0.0116 mmol)
were sequentially added to a Teflon-coated, stir bar containing Biotage 2-5
mL microwave reactor vial at room temperature and sealed with a septum.
An aliquot of PTS/H2O (1.0 mL; 2.5% PTS by weight; all cross-coupling
reactions were conducted at 0.5 M unless stated otherwise) was added via
syringe, and the resulting emulsion was allowed to stir at rt for 12 h. The
homogeneous reaction mixture was then diluted with EtOAc (5 mL) and
filtered through a bed of silica gel layered over Celite, and the bed was
washed (3 × 10 mL) with EtOAc. The volatiles were removed in vacuo to
afford the crude material, which was subsequently purified by flash
chromatography on silica gel (eluting with 10% EtOAc/hexanes) to yield
the product as a colorless oil (123 mg, 82%). The reported E/Z ratios were
determined by relative integrations of the olefinic resonances at 6.86 and
6.11 ppm. IR (neat): 3412, 2978, 2928, 2856, 1715, 1653, 1458, 1391,
(16) Choi, T-L.; Lee, C. W.; Chatterjee, A. K.; Grubbs, R. H. J. Am.
Chem. Soc. 2001, 123, 10417-10418.
(17) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783-3784.
(18) See the experimental procedure below and those in the Supporting
Information.
(19) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41,
3171-3174.
(20) (a) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2002, 41, 4035-4037. (b) Rivard, M.; Blechert, S. Eur. J.
Org. Chem. 2003, 2225-2228.
1
1367, 1315, 1158, 983 cm-1. H NMR (400 MHz, CDCl3): δ 6.86 (dt, J
(21) Randl, S.; Connon, S. J.; Blechert, S. Chem. Commun. 2001, 1796-
1797.
) 15.6, 6.8 Hz, 1H), 5.73 (dt, J ) 15.6, 1.2 Hz, 1H), 3.64 (q, J ) 6.4 Hz,
2H), 2.16 (qd, J ) 7.2, 1.2 Hz, 2H), 1.56 (quintet, J ) 7.2 Hz, 2H), 1.48
(s, 9H), 1.43 (quintet, J ) 7.2 Hz, 2H), 1.37-1.29 (m, 10H). 13C NMR
(100 MHz, CDCl3): δ 166.4, 148.4, 122.9, 80.1, 62.9, 32.8, 32.1, 29.55,
29.49, 29.4, 29.2, 28.2, 28.1, 25.8. MS (CI): m/z 271 (M + H, 66), 215
(100), 197 (88), 179 (15), 151 (20), 95 (29), 57 (98). HRMS (CI): calcd
for C16H31O3 [M + H]+ ) 271.2273, found 271.2282.
(22) (a) Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329-1332.
(b) Lipshutz, B. H.; Petersen, T. B.; Abela, A. R. Org. Lett. 2008, 10, 1333-
1336.
(23) (a) Griffin, W. C. J. Soc. Sosmet. Chem. 1949, 1, 311-326. (b)
Niraula, B. B.; Chun, T. K.; Othman, H.; Misran, M. Colloids Surf. A 2004,
248, 157-166.
(26) Sigma-Aldrich will offer PTS/H2O in May, 2008 (catalog #698717).
1328
Org. Lett., Vol. 10, No. 7, 2008