Rate enhanced olefin cross-metathesis reactions: The copper iodide effect

Article abstract of DOI:10.1021/jo200360s

Copper iodide has been shown to be an effective cocatalyst for the olefin cross-metathesis reaction. In particular, it has both a catalyst stabilizing effect due to iodide ion, as well as copper(I)-based phosphine-scavenging properties that apply to use o

Full text of DOI:10.1021/jo200360s

NOTE
pubs.acs.org/joc
Rate Enhanced Olefin Cross-Metathesis Reactions:
The Copper Iodide Effect
Karl Voigtritter, Subir Ghorai, and Bruce H. Lipshutz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
S Supporting Information
b
ABSTRACT: Copper iodide has been shown to be an effective
cocatalyst for the olefin cross-metathesis reaction. In particular, it
has both a catalyst stabilizing effect due to iodide ion, as well as
copper(I)-based phosphine-scavenging properties that apply to
use of the Grubbs-2 catalyst. A variety of Michael acceptors and
olefinic partners can be cross-coupled under mild conditions in
refluxing diethyl ether that avoid chlorinated solvents. This effect has also been applied to chemistry in water at room temperature
using the new surfactant TPGS-750-M.
he formation of carbonꢀcarbon double bonds by olefin
T
metathesis is among the most powerful and broadly applic-
able synthetic tools of modern organic chemistry.1 In particular,
cross-metathesis (CM) reactions promoted by ruthenium-based
catalysts have been widely utilized by synthetic organic as well
as polymer chemists in the construction of higher olefins from
simple alkene precursors.2 N-Heterocyclic carbene (NHC) ligand-
containing catalysts,3 such as the second-generation Grubbs cata-
lyst 14 (Figure 1), have emerged as especially promising in selec-
tive CM.5 For some conjugated olefins, however, reactions can be
rather challenging, most notably with vinyl ketones,6 acrylic acid,7
and acrylonitrile,8 oftentimes requiring higher loadings of catalyst
and heat. Although CuCl serves as phosphine scavenger to assist
with formation of GrubbsꢀHoveyda-19 or GrubbsꢀHoveyda-210
ruthenium carbene complexes, use of copper salts to enhance rates
of metathesis reactions themselves is rare.8,11 In this note we
describe a new procedure for carrying out CM reactions under the
beneficial impact of a copper(I) salt, CuI, which not only leads to
faster rates of cross-couplings but avoids chlorinated solvents
as well.
Figure 1. Structures of Ru-based catalysts used for olefin metathesis.
Figure 2 illustrates graphically the effect of CuI. The data
suggest that iodide ion may be serving an important role as a
stabilizing ligand on ruthenium, thereby extending the lifetime of
the original Grubbs-2 catalyst.11 To test this, an identical coupli-
ng with MVK was performed with NaI, which in fact led to the
same result as that seen with CuI (Scheme 1). Replacing MVK
with methyl acrylate to afford product 6 in the presence of NaI
alone led to the same positive outcome. However, the NaI effect
was not operative in the corresponding metathesis reactions
involving acrylic acid en route to product 7 (or acrylonitrile; vide
infra). Thus, while CuI gave complete conversion after 3 h, NaI
afforded only 64% consumption of educt 4. Curiously, switching
solvents from ether to DME, in which NaI is especially soluble,
the level of conversion for MVK dropped to 70% (from 100%)
and that for methyl acrylate to 67% (from 100%). Hence, unlike
previously studied additives and solvents, it appears that CuI in
ether provides both the ligand stabilizing effect of iodide on
ruthenium,12 as well as presumably a phosphine sequestering
effect by copper(I) from ruthenium.8
Several conditions and copper salts were screened utilizing a
TBS-protected allylphenol 4 as a representative substrate (Table 1).
Moving from CuCN (entry 1) to counterions with increased solubi-
lity in organic solvents (entries 2ꢀ8) showed little effect on turn-
over enhancement. An increase from 4% to 6 mol % of CuI showed
no effect (entry 13), while an increase in the Grubbs-2 catalyst
loading showed only modest improvement (entry 14). Changing
the solvent to toluene (entry 15) had no impact, while an improve-
ment was noted in both THF (entry 16) and diethyl ether (entry
17). Better results were obtained by diluting the latter ethereal
mixture from 0.5 to 0.1 M (entry 19). Ultimately, running the
reaction at 35 °C in refluxing Et2O for 3 h gave a nearly quantitative
yield (entry 21), while in the absence of CuI, the yield was only 57%.
The corresponding control reactions, each run in CH2Cl2 and Et2O
in the absence of CuI, clearly show an effect on the rate and extent
of reaction (entries 12 and 20).
Other olefin metathesis catalysts bearing phosphines were also
tested for reactivity in the presence of catalytic amounts of CuI
(Table 2). As noted previously, the Grubbs-2 catalyst showed a
remarkable near doubling in turnover when tested with CuI at
room temperature for 15 h (entry 1; see also Table 1, entries
Received: February 24, 2011
Published: April 29, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200360s J. Org. Chem. 2011, 76, 4697–4702
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Comparisons of NaI vs CuI in Olefin Cross-
Metathesis Reactions
Table 1. Optimizing Reaction Conditions
entry
CuX
solventa
conversion (%)b
1
2
CuCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
24
<5
0
CuOAc
3
Cu(OTf)2
Cu(BF4)2
Cu(NO3)2
Cu(ClO4)2
Cu(CF3COO)2
Cu(CH3CN)4PF6
CuCl
4
15
5
0
6
22
7
0
8
27
9
35
10
11
12
13c
14d
15
16
17
18e
19f
20f
21g
CuBr
43
CuI
64
45
CuI
CuI
CuI
CuI
CuI
CuI
CuI
63
68
64
70
Et2O
71
Et2O
76
Table 2. Screening of Alternative Ruthenium Catalysts
Et2O
85
Et2O
43
>99 (98)h
CuI
Et2O
a Reaction run in 0.5 M solution. b Based on 1H NMR. c Using 6 mol %
CuI. d Using 3 mol % Grubbs-2 and 6 mol % CuI. e Reaction run in 0.2 M
f
g
solution. Reaction run in 0.1 M solution. At 35 °C for 3 h; without
CuI; yield = 57%. h Isolated yield.
conversion (%)a
entry
catalyst
with CuI
without CuI
1
2
3
1
2
3
85
59
71
43
22
32
a Based on 1H NMR.
olefinic partners can be successfully cross-coupled in refluxing
ether at 0.1 M concentration within 3 h. Challenging cases,
such as acrylic acid and methyl vinyl ketone, readily participated
and led to high isolated yields, as did both methyl and tert-
butyl acrylate derivatives. An olefinic tetrazole15 and p-methoxy-
substituted allylbenzene each coupled smoothly with high E/Z
selectivities. Prospects for enyne cross-metathesis16 also look en-
couraging, with improved stereoselectivity due to the reduced tem-
peratures involved, as well as a reduced catalyst loading all being used
in a more attractive, nonchlorinated solvent (8, Scheme 2).17
Substituted furans 9 are also accessible via sequential CM/
acid-catalyzed cyclization, with lower levels of Grubbs-2 catalyst
loadings (Scheme 3).18
Selective and high-yielding CM using acrylonitrile remains a
challenge in olefin metathesis chemistry, presumably due to com-
petitive complexation of Ru by the nitrile group.19 Blechert has
studied this coupling reaction and finds that CuCl in the presence
of a Grubbs-2 precatalyst in refluxing CH2Cl2 leads to somewhat
improved results.8d Heating the reaction mixture, especially
Figure 2. Conversion versus time profile for the CM reaction between
olefin 4 and MVK with Grubbs-2 catalyst in Et2O, as measured by 1H
NMR [conditions: 0.1 M, 2 mol % Grubbs-2, with and without 3 mol %
CuI at room temperature].
19 vs 20). The less sterically encumbered, more reactive Grubbs
catalyst 213 (entry 2), as well as the Neolyst M2 catalyst14
(3, entry 3), showed similar increases in reactivity, but were
not pursued further due to the lower levels of conversions seen
relative to those noted with catalyst 1.
A series of olefins were screened under these newly developed
conditions (Table 3). As these examples indicate, a variety of
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NOTE
Table 3. CuI-Assisted Olefin Metathesis Reactionsa
Table 4. Effect of CuI on CM with Acrylonitrile
entry
acrylonitrile (equiv)
time (h)
conversion (%)a
1
5.0
1.5
1.5
1.5
1.5
1.5
1.5
24
3
35
38b
2
3c
4c
5d
6d,f
7d,g
1
53
3
60
64 (51)e
3
3
61
3
30
a Based on H NMR. b Significant amount of starting material dimer
formed. c Grubbs-2 catalyst added as a solution over 30 min. d Grubbs-2
catalyst added portionwise as a solid over 2 h. e Isolated yield. f 8 mol %
CuI. g No CuI added.
1
Scheme 4. Effect of NaI on CM with Acrylonitrile
c
a Reactions were conducted at 0.5 mmol scale. b Isolated yields. E/Z
ratio was determined by 1H NMR.
Scheme 2. Cross Enyne Metathesis with Allyl Alcohol
Scheme 5. Copper-Assisted Cross-Metathesis on Osthole
Scheme 3. One-Pot Synthesis of a Substituted Furana
Best results were obtained under these conditions (entries 4 and 5).
As before, increasing the amount of copper did not improve the
conversion to product (entry 6); leaving copper out of the
reaction entirely cut the conversion in half (entry 7). Using
NaI alone gave poor levels of conversion with 3, or even 6, mol %
of this additive (Scheme 4).
a Reagents and conditions: (i) Grubbs-2 (2 mol %), CuI (3 mol %),
Et2O, 35 °C, 3 h. (ii) PPTS (2.5 mol %), CH2Cl2, 40 °C, 12 h.
Opportunities to apply the CuI effect to cross-metathesis
reactions involving trisubstituted olefins of the isopropylidene
variety also exist, and while uncommon in general, could prove
especially useful.21 A challenging reaction between this Type III
olefin and a Type II acrylate was attempted on the natural prod-
uct osthole, 11, an antiplatelet agent that inhibits phosphoinosi-
tide breakdown.22 As shown in Scheme 5, the desired tert-butyl
acrylate 12 (all E) was formed in good yield (81%, quant. brsm)
under standard conditions in refluxing ether over 24 h.
under microwave conditions, can also be very effective in such
reactions.20 An initial attempt with, typically, an excess of the
nitrile under optimized conditions in refluxing ether led to a
discouraging 35% conversion to 10, even after extended reaction
times (Table 4, entry 1). Reducing the nitrile concentration led
to an increase in homocoupling with the type I olefinic partner,
as well as a slight increase in the nitrile CM products (E þ Z;
entry 2). To maximize the production of the desired unsaturated
nitrile and minimize any decomposition of the highly reactive,
phosphine-free Ru complex, the catalyst was added over time.
Lastly, we have recently reported that the amphiphile “TPGS-
750-M” (13),23 present only to the extent of ca. 2.5% (by weight),
allows for cross-metathesis to take place within nanometer micelles
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NOTE
Table 5. CuI-Assisted Olefin Metathesis Reactions in Water
reflux condenser. The solution was heated at 40 °C (oil bath tempera-
ture) for 3 h. After cooling to room temperature, the reaction mixture
was concentrated in vacuo and the residue was purified by column
chromatography, under the conditions noted, to afford the correspond-
ing metathesis adduct.
at Room Temperaturea
(E)-4-(2-(tert-Butyldimethylsilyloxy)phenyl)but-2-enoic Acid
(Table 3, entry 1). The general procedure above was followed, using tert-
butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50 mmol), acrylic acid
(72.1 mg, 1.0 mmol), Grubbs-2 catalyst (8.5 mg, 10.0 μmol), and CuI
(2.9 mg, 15.0 μmol). Column chromatography on silica gel (eluting with
30% EtOAc/hexanes) afforded the product as a white solid (133 mg, 82%).
Mp 81ꢀ83 °C; IR (thin-film): 3022, 2955, 2930, 2859, 1697, 1649, 1492,
1263, 926 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.23 (dt, J = 15.6, 6.4 Hz,
1H), 7.14 (dt, J = 7.5, 1.8 Hz, 1H), 7.10 (dd, J = 7.5, 1.8 Hz, 1H), 6.91 (dt,
J = 7.5, 1.1 Hz, 1H), 6.83 (dd, J = 8.1, 1.1 Hz, 1H), 5.76, (dt, J = 15.6, 1.8 Hz,
1H), 3.54, (dd, J = 6.4, 1.6 Hz, 2H), 1.01 (s, 9H), 0.26 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 172.5, 153.7, 150.5, 130.7, 128.2, 128.1, 121.5, 121.4,
118.6, 33.4, 26.0, 18.4, ꢀ3.9; ESI-MS m/z 315 (M þ Na); HRMS (ESI)
calcd for C16H24O3SiNa [M þ Na]þ 315.1392, found 315.1395.
(E)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)pent-3-en-2-one
(Table 3, entry 2). The general procedure above was followed, using tert-
butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50 mmol), methyl vinyl
ketone (106 mg, 1.50 mmol), Grubbs-2 catalyst (8.5 mg, 10.0 μmol), and
CuI (2.9 mg, 15.0 μmol). Column chromatography on silica gel (eluting
with 3% EtOAc/hexanes) afforded the product as a colorless oil (142 mg,
98%). IR (neat) 3062, 3034, 2932, 2894, 2859, 1699, 1676, 1626, 1599,
1582, 1492, 1472, 1452, 1422, 1390, 1361, 1254, 1182, 1108, 1043, 982,
929 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.15 (td, J = 7.6, 1.6 Hz, 1H),
7.11 (dd, J = 7.6, 1.6 Hz, 1H), 6.95 (dt, J = 16.0, 6.4 Hz, 1H), 6.92 (td, J =
7.6, 1.2 Hz, 1H), 6.84 (dd, J = 7.6, 1.2 Hz, 1H), 6.03 (dt, J = 16.0, 1.6 Hz,
1H), 3.54 (dd, J = 6.4, 1.6 Hz, 2H), 2.24 (s, 3H), 1.01 (s, 9H), 0.26 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 198.8, 153.7, 146.8, 132.0, 130.7, 128.4,
128.1, 121.4, 118.6, 33.7, 26.9, 25.9, 18.4, ꢀ4.0; EI-MS m/z (%) 275 (M ꢀ
CH3þ, 2), 233 (M ꢀ C4H9þ, 100), 215 (20), 151 (8), 75 (42); HRMS
(EI) calcd for C13H17O2Si [M ꢀ C4H9]þ 233.0998, found 233.1006.
(E)-tert-Butyl 4-(2-(tert-Butyldimethylsilyloxy)phenyl)-2-
butenoate (Table 3, entry 3). The general procedure above was
followed, using tert-butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50
mmol), tert-butyl acrylate (192 mg, 1.50 mmol), Grubbs-2 catalyst
(8.5 mg, 10.0 μmol), and CuI (2.9 mg, 15.0 μmol). Column chromatog-
raphy on silica gel (eluting with 3% EtOAc/hexanes) afforded the product
as a pale yellow oil (162 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.15ꢀ
7.10 (m, 2H), 7.00 (dt, J = 15.6, 6.4 Hz, 1H), 6.91 (dt, J = 7.6, 1.2 Hz, 1H),
6.82 (dd, J = 8.0, 0.8 Hz, 1H), 5.68 (dt, J = 15.6, 1.6 Hz, 1H), 3.48 (dd, J =
6.4, 1.6 Hz, 2H), 1.46 (s, 9H), 1.01 (s, 9H), 0.25 (s, 6H).8a
(E)-Methyl 4-(2-(tert-Butyldimethylsilyloxy)phenyl)but-2-
enoate (Table 3, entry 4). The general procedure above was followed,
using tert-butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50 mmol), methyl
acrylate (129 mg, 1.50 mmol), Grubbs-2 catalyst (8.5 mg, 10.0 μmol), and
CuI (2.9 mg, 15.0 μmol). Column chromatography on silica gel (eluting
with 3% EtOAc/hexanes) afforded the product as a pale yellow oil (143 mg,
93%). IR (neat) 3063, 3023, 2953, 2931, 2859, 1726, 1656, 1492, 1265,
1161, 930; 1H NMR (400 MHz, CDCl3) δ 7.16ꢀ7.08 (m, 3H), 6.90 (dt,
J = 7.2, 1.1 Hz, 1H), 6.82 (dd, J = 8.2, 1.1 Hz, 1H), 5.77 (dt, J = 15.6, 1.8
Hz, 1H), 3.72 (s, 3H), 3.51 (dd, J = 6.3, 1.5 Hz, 2H), 1.01 (s, 9H), 0.25
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 167.1, 153.6, 147.8, 130.6,
128.5, 128.0, 122.0, 121.4, 119.0, 51.5, 33.2, 25.9, 18.4, ꢀ4.0; FI-MS m/z
306 [M]þ, 249 [M ꢀ C4H9]þ; HRFIMS calcd for C17H26O3Si [M]þ
306.1651, found 306.1645.
a Reactions were conducted at 0.5 mmol scale. b Isolated yields. c 3 mol %
CuI.
in water as the gross reaction medium.24 As illustrated by several
examples in Table 5, the benefits ascribed to the presence of CuI
can be realized as well under conditions of micellar catalysis25 by
using this new nonionic surfactant.
In summary, the positive impact of catalytic quantities of CuI
in cross-metathesis reactions mediated by the Grubbs-2 catalyst
has been demonstrated, in particular where more challenging
Type II and Type III olefinic reaction partners are involved (e.g.,
MVK, acrylic acid, acrylonitrile, and isopropylidene derivatives).
These couplings are done in ethereal solvent, rather than
chlorinated media, as the former is preferred both insofar as
the chemistry is concerned, and from the environmental perspec-
tive.26 It has also been shown that equally effective couplings can
be achieved by using micellar catalysis conditions, where CM
within nanoparticles takes place in water at room temperature.
’ EXPERIMENTAL SECTION
General Procedure for Cross-Metathesis Reactions in
Et2O. A flame-dried pear-shaped flask with a rubber septum contain-
ing a stir bar was charged with alkene (0.50 mmol), acrylate/ketone
(1.50 mmol), Grubbs-2 catalyst (8.5 mg, 10.0 μmol), and CuI (2.9 mg,
15.0 μmol) under an Ar atmosphere. Freshly distilled ethyl ether
(5.0 mL) was added, and the rubber septum was then replaced with a
(E)-tert-Butyl 6-(1-Phenyl-1H-tetrazol-5-ylthio)-2-hexeno-
ate (Table 3, entry 5). The general procedure above was followed,
using 5-(pent-4-en-1-ylthio)-1-phenyl-1H-tetrazole8a (123 mg, 0.50 mmol),
tert-butyl acrylate (192 mg, 1.50 mmol), Grubbs-2 catalyst (8.5 mg,
10.0 μmol), and CuI (2.9 mg, 15.0 μmol). Column chromatography on
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NOTE
silica gel (eluting with 10% EtOAc/hexanes) afforded the product as a
colorless oil (145 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 7.57ꢀ7.53
(m, 5H), 6.80 (dt, J = 15.6, 7.2 Hz, 1H), 5.77 (dt, J = 15.6, 1.6 Hz, 1H),
3.39 (t, J=7.2Hz,2H),2.33(qd,J= 6.8, 1.6 Hz, 2H), 2.01 (quintet, J=7.6Hz,
2H), 1.46 (s, 9H).8a
2931, 2843, 1734, 1713, 1605, 1287, 1253, 1119, 1103 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 7.63 (d, J = 9.2 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H),
6.94 (dt, J = 15.4, 6.6 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.22 (d, J = 9.3 Hz,
1H), 5.67 (dt J = 15.6, 1.7 Hz, 1H), 3.91 (s, 3H), 3.71 (d, J = 1.7 Hz, 2H),
1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 166.3, 161.3, 160.5, 153.1,
144.3, 143.9, 127.5, 123.7, 114.1, 113.3, 113.1, 107.5, 80.3, 56.3, 28.3, 25.3;
ESI-MS m/z 355 (M þ K), 339 (M þ Na); HRMS (ESI) calcd for
C18H20O5Na [M þ Na]þ 339.1208, found 339.1195.
(E)-Methyl 4-(4-Methoxyphenyl)-2-butenoate (Table 3,
entry 6). The general procedure above was followed, using 4-allylani-
sole (74 mg, 0.50 mmol), methyl acrylate (129 mg, 1.50 mmol), Grubbs-
2 catalyst (8.5 mg, 10.0 μmol), and CuI (2.9 mg, 15.0 μmol). Column
chromatography on silica gel (eluting with 2.5% EtOAc/hexanes)
General Procedure for Cross-Metathesis Reactionsin Water.
Alkene (0.50 mmol), acrylate (1.00 mmol)/ketone (1.50 mmol), CuI
(2.9 mg, 15.0 μmol), and Grubbs-2 catalyst (8.5 mg, 10.0 μmol) were
sequentially added into a Teflon-coated, stir bar-containing Biotage
2ꢀ5 mL microwave reactor vial at rt, which was then sealed with a septum.
An aliquot of TPGS-750-M/H2O (1.0 mL; 2.5% TPGS-750-M by weight;
all cross-coupling reactions were conducted at 0.5 M unless stated other-
wise) was added, via syringe, and the resulting solution was allowed to stir
at rt for 12ꢀ20 h. The homogeneous reaction mixture was then diluted
with EtOAc (2 mL) and filtered through a bed of silica gel, thenthe bedwas
further washed (3 ꢁ 3 mL) with EtOAc to collect all of the cross-coupled
material. The volatiles were removed in vacuo to afford the crude product
that was subsequently purified by flash chromatography on silica gel.
(E)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)pent-3-en-2-one
(Table 5, entry 1). The general procedure above was followed, using tert-
butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50 mmol), methyl vinyl
ketone (106 mg, 1.50 mmol), CuI (2.9 mg, 15.0 μmol), and Grubbs-2
catalyst (8.5 mg, 10.0 μmol). Column chromatography on silica gel (eluting
with 3% EtOAc/hexanes) afforded the product as a colorless oil (135 mg,
93%). 1H NMR (400 MHz, CDCl3) δ 7.15 (td, J = 7.6, 1.6 Hz, 1H), 7.11
(dd, J = 7.6, 1.6 Hz, 1H), 6.95 (dt, J = 16.0, 6.4 Hz, 1H), 6.92 (td, J = 7.6, 1.2
Hz, 1H), 6.84 (dd, J = 7.6, 1.2 Hz, 1H), 6.03 (dt, J = 16.0, 1.6 Hz, 1H), 3.54
(dd, J = 6.4, 1.6 Hz, 2H), 2.24 (s, 3H), 1.01 (s, 9H), 0.26 (s, 6H).
(E)-tert-Butyl 3-(2,4-Dimethylphenyl)acrylate (Table 5, entry
2). The general procedure above was followed, using 2,4-dimethyl-1-
vinylbenzene (66 mg, 0.50 mmol), tert-butyl acrylate (128 mg, 1.00 mmol),
CuI (2.9 mg, 15.0 μmol), and Grubbs-2 catalyst (8.5 mg, 10.0 μmol).
Column chromatography on silica gel (eluting with 2% EtOAc/hexanes)
afforded the product as a colorless oil (97 mg, 84%). 1H NMR (400 MHz,
CDCl3) δ7.87 (d, J= 15.6 Hz, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.03ꢀ7.01 (m,
2H), 6.29 (d, J = 15.6 Hz, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.55 (s, 9H).8a
(E)-13-(tert-Butyldimethylsilyloxy)tridec-3-en-2-one (Table 5,
entry 3). The general procedure above was followed, using tert-
butyldimethyl(undec-10-enyloxy)silane10a (144 mg, 0.50 mmol), methyl
vinyl ketone (106 mg, 1.50 mmol), CuI (2.9 mg, 15.0 μmol), and Grubbs-
2 catalyst (8.5 mg, 10.0 μmol). Column chromatography on silica gel
(eluting with 3% EtOAc/hexanes) afforded the product as a colorless oil
(146 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 6.80 (dt, J = 16.0, 6.8 Hz,
1H), 6.06 (d, J = 16.0 Hz, 1H), 3.59 (t, J = 6.8 Hz, 2H), 2.24 (s, 3H), 2.21
(q, J = 7.2 Hz, 2H), 1.53ꢀ1.42 (m, 4H), 1.28 (br s, 10H), 0.89 (s, 9H),
0.04 (s, 6H).10a
1
afforded the product as a colorless oil (97 mg, 94%). H NMR (400
MHz, CDCl3) δ 7.13ꢀ7.06 (m, 3H), 6.86 (d, J = 8.8 Hz, 2H), 5.80 (dt,
J = 15.6, 1.6 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.47 (d, J = 6.8 Hz, 2H).8a
(E)-4-Methylene-6-(triisopropylsilyloxy)hex-2-en-1-ol (8).
The general procedure above was followed, using (but-3-yn-1-yloxy)-
triisopropylsilane (106.2 mg, 0.50 mmol), prop-2-en-1-ol (174.2 mg,
3.00 mmol), Grubbs-2 catalyst (8.5 mg, 10.0 μmol), and CuI (2.9 mg,
15.0 μmol). Column chromatography on silica gel (eluting with 20%
EtOAc/hexanes) afforded the product as a pale yellow oil (106 mg, 80%,
E/Z = 6:1). IR (neat) 3337, 3083, 2943, 2867, 1684, 1607, 1464, 1384,
1104, 883 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 6.27 (d, J = 16.1 Hz,
1H), 5.89 (dt, J = 15.8, 5.8 Hz, 1H), 5.07 (s, 1H), 5.03 (s, 1H), 4.22 (br t,
J = 4.0 Hz, 2H), 3.81 (t, J = 7.0 Hz, 2H), 2.49 (dt, J = 7.4, 0.9 Hz, 2H),
1.07ꢀ1.05 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 142.5, 133.5,
128.1, 117.4, 63.7, 62.8, 35.9, 18.2, 12.2;FI-MS m/z 284 [M]þ, 241 [M ꢀ
C3H7]þ;HRFIMScalcdforC16H32O2Si [ M]þ 284.2172, found 284.2179.
2-Ethyl-5-phenethylfuran (9). A flame-dried pear-shaped flask
with a rubber septum containing a stir bar was charged with 5-phenylpent-
1-en-3-ol (41 mg, 0.25 mmol), ethyl vinyl ketone (53 mg, 0.63 mmol),
Grubbs-2 catalyst (4.2 mg, 5.0 μmol), and CuI (1.4 mg, 7.5 μmol) inEt2O
(2.5 mL) under an argon atmosphere. The rubber septum was then
replaced with a reflux condenser and the solution was heated at 40 °C (oil
bath temperature) for 3 h. After cooling toroom temperature, the reaction
mixture was concentrated in vacuo. PPTS (1.6 mg, 6.3 μmol) and CH2Cl2
(1 mL) were added and the reaction was allowed to stir for an additional
12 h at40 °C. Aftercoolingto room temperature, thereactionmixture was
concentratedin vacuo. Column chromatography onsilicagel(eluting with
2% EtOAc/hexanes) afforded the product as a colorless oil (34 mg, 68%).
1H NMR (400 MHz, CDCl3) δ 7.32ꢀ7.27 (m, 2H), 7.23ꢀ7.18 (m, 3H),
5.88ꢀ5.85 (m, 2H), 2.98ꢀ2.93 (m, 2H), 2.92ꢀ2.86 (m, 2H), 2.63 (q, J =
7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H).17
(Z)-4-(2-(tert-Butyldimethylsilyloxy)phenyl)but-2-enenitrile
(10). The general procedure above was followed, using tert-butyl(2-
allylphenoxy)dimethylsilane (124 mg, 0.50 mmol), acrylonitrile (39.8 mg,
0.75 mmol), Grubbs-2 catalyst (8.5 mg, 10.0 μmol), and CuI (2.9 mg,
15.0 μmol). Column chromatography on silica gel (eluting with 3%
EtOAc/hexanes) afforded the product as a colorless oil (70 mg, 51%,
Z/E = 3.3:1.0). IR (neat) 3067, 3035, 2956, 2931, 2896, 2859, 2222,
1683, 1620, 1599, 1583, 1492, 1472, 1454, 1390, 1362, 1258, 1184, 1109,
1045, 1108, 928, 838 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.17ꢀ7.14
(m, 2H), 6.93 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.65 (dt, J =
11.2, 7.2 Hz, 1H), 5.38 (d, J = 11.2 Hz, 1H), 3.74 (d, J = 7.2 Hz, 2H), 1.03
(s, 9H), 0.27(s, 6H); 13CNMR (100 MHz, CDCl3) δ 153.3, 130.8, 130.4,
128.6, 128.4, 121.6, 118.7, 116.3, 99.7, 34.4, 33.2, 26.0, ꢀ3.9; FI-MS m/z
273 [M]þ, 216 [M ꢀ C4H9]þ; HRFIMS calcd for C16H23NOSi [M]þ
273.1549, found 273.1557.
(E)-tert-Butyl 6-(1-Phenyl-1H-tetrazol-5-ylthio)-2-hexeno-
ate (Table 5, entry 4). The general procedure above was followed,
using 5-(pent-4-en-1-ylthio)-1-phenyl-1H-tetrazole8a (123 mg, 0.50 mmol),
tert-butyl acrylate (192 mg, 1.50 mmol), CuI (7.2 mg, 38.0 μmol), and
Grubbs-2 catalyst (21.2 mg, 25.0 μmol). Column chromatography on
silica gel (eluting with 10% EtOAc/hexanes) afforded the product as a
colorless oil (138 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.59ꢀ7.55
(m, 5H), 6.82 (dt, J = 15.6, 7.2 Hz, 1H), 5.79 (dt, J = 15.6, 1.6 Hz, 1H),
3.41 (t, J = 7.2 Hz, 2H), 2.36 (qd, J = 7.2, 1.6 Hz, 2H), 2.03 (quintet, J =
7.2 Hz, 2H), 1.48 (s, 9H).8a
(E)-2-Adamantyl 4-(4-Methoxyphenyl)-2-butenoate (Table 5,
entry 5). The general procedure above was followed, using 4-allylani-
sole (74 mg, 0.50 mmol), 2-adamantyl acrylate (206 mg, 1.00 mmol),
CuI (2.9 mg, 15.0 μmol), and Grubbs-2 catalyst (8.5 mg, 10.0 μmol).
Column chromatography on silica gel (eluting with 5% EtOAc/hexanes)
(E)-tert-Butyl 4-(7-Methoxy-2-oxo-2H-chromen-8-yl)but-
2-enoate (12). The general procedure above was followed, using
osthole (11) (40 mg, 0.16 mmol), tert-butyl acrylate (63 mg, 0.49 mmol),
Grubbs-2 catalyst (4.2 mg, 4.91 μmol), and CuI (1.4 mg, 7.37 μmol). The
catalyst and acrylate were added over time and the solution was allowed to
stir for 24 h at 40 °C (oil bath temperature). Column chromatography on
silica gel (eluting with 10% EtOAc/hexanes) afforded the product as a
white solid (42 mg, 81%). Mp 137ꢀ140 °C; IR (thin-film) 3071, 2979,
4701
dx.doi.org/10.1021/jo200360s |J. Org. Chem. 2011, 76, 4697–4702

The Journal of Organic Chemistry
NOTE
1
afforded the product as a colorless oil (145 mg, 89%). H NMR (400
MHz, CDCl3) δ 7.16ꢀ7.08 (m, 3H), 6.88 (d, J = 8.8 Hz, 2H), 5.84 (dt,
J = 15.2, 1.2 Hz, 1H), 4.99 (br s, 1H), 3.80 (s, 3H), 3.47 (dd, J = 6.8, 1.2
Hz, 2H), 2.05ꢀ2.01 (m, 4H), 1.90ꢀ1.74 (m, 8H), 1.58ꢀ1.56 (m, 2H).8a
119, 3887–3897. (c) Sanford, M. S.; Henling, L. M.; Grubbs, R. H.
Organometallics 1998, 17, 5384–5389.
(12) (a) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc.
2006, 128, 1840–1846. (b) Wappel, J.; Urbina-Blanco, C. A.; Abbas, M.;
Albering, J. H.; Saf, R.; Nolan, S. P.; Slugovc, C. Beilstein J. Org. Chem.
2010, 6, 1091–1098.
(13) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592.
’ ASSOCIATED CONTENT
Supporting Information. Copies of H and 13C NMR
1
S
(14) (a) Hurley, P. B.; Dake, G. R. J. Org. Chem. 2008, 73, 4131–
4138. (b) Verpoort, F.; Opstal, T. New J. Chem. 2003, 27, 257–262.
(15) Numerous previous attempts (by varying reaction temperature
and the amount of catalyst) to drive this coupling beyond the 55%
reported had not been successful. See ref 8a.
b
spectra of all new compounds and copies of 1H NMR spectra of
all known compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) (a) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1–18.(b) Mori,
M. EneꢀYne Metathesis. In Handbook of Metathesis; Grubbs, R. H.,
Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 2, pp 176ꢀ204.
(c) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317–1382.
(17) Clark, D. A.; Clark, J. R.; Diver, S. T. Org. Lett. 2008, 10,
2055–2058.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu.
(18) Donohoe, T. J.; Bower, J. F. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 3373–3376.
’ ACKNOWLEDGMENT
(19) Bai, C.-X.; Lu, X.-B.; He, R.; Zhang, W.-Z.; Feng, X.-J. Org.
Biomol. Chem. 2005, 3, 4139–4142.
(20) Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem. 2008, 1125–1132.
(21) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
Financial support provided by the NSF (CHE 0948479) and
NIH (GM 86485) is warmly acknowledged. We also thank Dr.
Richard Pederson (Materia) and Dr. Oliver Briel (Umicore) for
supplying the Grubbs and Neolyst catalysts, respectively, used in
this study.
(22) Okamoto, T.; Kawasaki, T.; Hino, O. Biochem. Pharmacol.
2003, 65, 677–681.
(23) TPGS-750-M will be offered in February, 2011, as a 2 wt %
solution in water by Sigma-Aldrich. This product will be listed under
catalog no. 733857.
(24) Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata,
T.; Duplais, C.; Krasovskiy, A.; Gatson, R. D.; Gadwood, R. C. J. Org.
Chem. 2011, DOI: (http://dx.doi.org/10.1021/jo101974u).
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2005, 44, 7174–7199.(b) Khan, M. N. Micellar Catalysis; CRC Press:
Boca Raton, FL, 2006.
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dx.doi.org/10.1021/jo200360s |J. Org. Chem. 2011, 76, 4697–4702