Ring-closing metathesis at room temperature within nanometer micelles using water as the only solvent

Article abstract of DOI:10.1002/adsc.200800114

Simply mixing a water-insoluble diolefinic substrate and Grubbs second generation catalyst in pure water containing small amounts of the amphiphile polyoxyethanyl α-tocopheryl sebacate (PTS) leads to efficient ring-closing metathesis.

Full text of DOI:10.1002/adsc.200800114

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DOI: 10.1002/adsc.200800114
Ring-Closing Metathesis at Room Temperature within Nanometer
Micelles using Water as the Only Solvent
a,
a
a
Bruce H. Lipshutz, * Subir Ghorai, and Grant T. Aguinaldo
a
Department of Chemistry& Biochemistr y, Universityof California, Santa Barbara, CA 93106, USA
Fax : (+1)-805-893-8265; e-mail: lipshutz@chem.ucsb.edu
Received: February21, 2008; Published online: March 20, 2008
Dedicated to Professor Andreas Pfaltz on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Simplymixing a water-insoluble diolefinic
substrate and Grubbs second generation catalyst in
pure water containing small amounts of the amphi-
phile polyoxyethanyl a-tocopheryl sebacate (PTS)
leads to efficient ring-closing metathesis.
tant; that water alone could in manycases afford cy-
clized products in high yields. Recently, the 3-compo-
nent amphiphile PTS (1, (polyoxyethanyl a-tocopher-
yl sebacate) has been introduced as a “general pur-
Keywords: amphiphiles; nanomicellar catalysis;
polyoxyethanyl a-tocopheryl sebacate (PTS); ring-
closing metathesis; surfactants
Although there are arguments as to the pros and cons
of water as a solvent for organic reactions, the situa- pose” nonionic amphiphile, allowing for Heck,
[
1]
[9]
[
10]
tion is made all the more confusing given the options Suzuki,
and olefin cross-metathesis (CM) reac-
with water,ꢁ ꢀin water,ꢁ and ꢀon water.ꢁ The sim- tions to occur with lipophilic substrates also in pure
plest approach would be to relyon water alone; i.e., water at room temperature. Unsymmetrical CM reac-
with no co-solvents involved whatsoever. Of course, tions were shown to proceed far better under the in-
[2]
[3]
[4,5]
[11]
ꢀ
[
4,5,8]
depending upon reaction type, substrates, additives, fluence of PTS than ꢀon waterꢁ,
reactions presum-
catalysts and other possible parameters, solubility ablytaking place within the ca. 25 nanometer micelles
[
12,13]
issues can overshadow opportunities for the exclusive formed. In this report RCM reactions
are de-
use of water as solvent. One remarkablysimple po- scribed, using minimal amounts of PTS in water at
tential solution relies on the presence of an amphi- ambient temperatures, along with a far more reactive
phile that “dissolves” otherwise water-insoluble reac- yet commercially available ruthenium catalyst
tion components within its micellar lipophilic core (Scheme 1).
[
6]
that has self-assembled in aqueous media. If an ap-
propriate surfactant is identified, reactions maybene-
fit not onlyin terms of ease of handling, but also with
Aqueous solutions containing only1.5–2.5% PTS
(byweight) served admirablyas reaction media for a
varietyof diolefinic educts, as illustrated in Table 1.
[
7]
[14]
respect to rates accelerated bymicellar catal ys is.
002, Davis and Sinou studied the effect of several be used as received from commercial sources. Ad-
In The Grubbs second generation catalyst (2%) could
[15]
2
phase-transfer catalysts and both ionic (e.g., SDS; dition of both starting material and catalyst to PTS in
[
14d]
sodium dodecyl sulfate) and nonionic surfactants water can be carried out in air.
Likewise, these
(
e.g., Brij 35; decaoxyethylene dodecyl ether), on RCM reactions do not require inert atmosphere con-
ring-closing metathesis (RCM) reactions in water ditions. Efficient stirring at room temperature over a
with the Grubbs-1 catalyst under very carefully con- few hours at concentrations of ca. 0.1M usuallyleads
trolled conditions (Schlenk techniques, distilled, de- to complete consumption of starting materials and
[
8]
ionized, and degassed water, etc.). Their conclusion very clean, high yielding cyclizations. Ring sizes com-
was that such reactions maynot require anysurfac- posed of 5- (entries A, B, E, F), 6- (entryC), and 7-
Adv. Synth. Catal. 2008, 350, 953 – 956
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
953

Bruce H. Lipshutz et al.
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A) can be realized. Amine-derivatized precursors in-
clude N-arylsulfonyl (entries B–D, F) or benzoyl ex-
amples (entryE). Remarkabl y, on increasing the over-
all reaction concentration from 0.1M to 0.3M in
water, thus decreasing the amount of PTS to 0.8%
(
byweight), the reaction rate and efficiencyremained
unchanged (e.g., in the case of entryB).
,5-Dihydropyrroles can result from N-allylated sul-
2
fonamides of varying substitution patterns on one or
both of the double bonds. Thus, in addition to a sym-
metricallysubstituted diall lya mine ( 2), methyl- and
dimethylated analogues
3
and 4, respectively
(
Scheme 2), gave the expected identical product 5 in
comparable yields. Use of prenylated amine 4 is par-
ticularlynoteworth ,y and is suggestive that such ter-
minallydisubstituted olefins can also be used in (pre-
viouslyunprecedented) RCM reactions. Reaction
work-up and product isolation free of anyPTS is very
straightforward, a general observation as noted in
Scheme 1. Ring-closing metathesis affording di-, tri- or tetra-
substituted cycloalkenes.
Table 1. Ring-closing metathesis reactions in 2.5% PTS/
[
9–11]
[a]
A
H
R
U
G
(also, see proce-
water.
Formation of trisubstituted alkene derivatives
within both 5- and 6-membered rings, products un-
available previouslydue to reliance on the less reac-
[
8]
tive Grubbs-1 catalyst, took place uneventfullyin
veryhigh yi elds (Scheme 3). In the case of metathesis
of methallylated amine 6 (in 2.5% PTS/H O, 97%
2
yield), the corresponding reaction ꢀon waterꢁ (i.e., in
Scheme 2. Ring-closing metathesis on variouslysubstituted
allylic amines.
[
[
a]
b]
2
mol% Grubbs 2nd generation catalyst at 0.1M at 228C
for 3 h.
Isolated yield of chromatographically purified material.
members (entryD) are smoothlyformed. Both heter-
oatom (entries B–F) and non-heteroatom rings (entry Scheme 3. RCM forming trisubstituted olefins in PTS/water.
954
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Adv. Synth. Catal. 2008, 350, 953 – 956

Ring-Closing Metathesis at Room Temperature within Nanometer Micelles
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[
4]
water but in the absence of PTS) led to an 80% which was subsequentlypurified byflash chromatography
on silica gel (12% EtOAc/hexanes) to furnish the product as
a white solid; yield: 41 mg (96%); mp 86–888C; IR (thin
yield of product 7 under otherwise identical condi-
tions. The homologue of 6, sulfonamide 8, efficiently
closed to 9 essentiallyquantitatively.
One case of a tetrasubstituted olefin was studied,
focused on educt 10. As expected, metathesis was far
slower, requiring heating to 608C over 24 h to afford
film): n=2971, 2912, 2876, 1744, 1483, 1470, 1415, 1403,
À1
1
379, 1331, 1217, 1146, 1111, 1051, 982, 966, 945 cm ;
1
H NMR (400 MHz, CDCl ): d=5.78 (t, J=4.0 Hz, 2H),
3
4
1
.26–4.17 (m, 4H), 3.38 (d, J=14.8 Hz, 1H), 2.81 (d, J=
4.8 Hz, 1H), 2.52 (ddd, J=14.4, 11.5, 4.0 Hz, 1H), 2.37 (dt,
1
1 in a modest 66% isolated yield. Most of the re-
J=18.4, 4.0 Hz, 1H), 2.09 (t, J=4.8 Hz, 1H), 2.07–1.99 (m,
1H), 1.92 (d, J=18.4 Hz, 1H), 1.64 (ddd, J=14.4, 9.6,
maining mass was starting material.
4
3
1
1
.8 Hz, 1H), 1.41 (ddd, J=12.4, 9.2, 4.0 Hz, 1H), 1.12 (s,
1
3
H), 0.88 (s, 3H); C NMR (100 MHz, CDCl ): d=215.8,
3
25.8, 58.4, 55.0, 48.1, 44.7, 42.92, 42.76, 27.1, 25.3, 20.1,
9.9; MS (CI): m/z (%)=284 (M + H, 21), 215 (18), 151
(
2
11), 123 (12), 109 (20), 68 (100); HR-MS (CI): m/z=
84.1322, calcd. for C H NO S [M + H] : 284.1320.
14 22 3
+
Acknowledgements
In summary, an especially simple methodology has
Financial support generously provided by Zymes, LLC is
been uncovered that allows for ring-closing metathe- warmly acknowledged with thanks.
sis reactions involving lipophilic substrates and a
highlyactive, water-insoluble ruthenium catal ys t to be
effected at room temperature in water as the only
medium. The virtues of this technologyinclude (1)
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