Tandem olefin metathesis-elimination reactions. A new route to doubly unsaturated carbonyl derivatives

Article abstract of DOI:10.1016/j.tet.2008.04.027

Cross-metathesis between an activated olefin and an ethereal derivative of homoallylic alcohols leads to products that are subject to facile elimination resulting in α,β,γ,δ-unsaturated esters, ketones, acids, and aldehydes in high yields.

Full text of DOI:10.1016/j.tet.2008.04.027

Tetrahedron 64 (2008) 6949–6954
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem olefin metathesis–elimination reactions. A new route to doubly
unsaturated carbonyl derivatives
*
ˇ
ˇ
´
Bruce H. Lipshutz , Subir Ghorai, Zarko V. Boskovic
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106 USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Cross-metathesis between an activated olefin and an ethereal derivative of homoallylic alcohols leads to
Received 10 January 2008
Received in revised form 28 March 2008
Accepted 7 April 2008
products that are subject to facile elimination resulting in
aldehydes in high yields.
a,b,g,d-unsaturated esters, ketones, acids, and
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 11 April 2008
R
R'
1. Introduction
O
+
LG
Harnessing the power of olefin metathesis chemistry1 has led to
a wealth of new opportunities in organic synthesis. As these are
oftentimes ruthenium-catalyzed processes, additional advantage
can be taken of the metal for further bond constructions in a
one-pot tandem fashion. Some recent examples of such sequential
catalysis include a cross-metathesis (CM)/Wittig olefination by
Murelli and Snapper,2a and Paul and Andrade,2b ring-closing me-
tathesis (RCM) or CM/cis-dihydroxylation from Blechert’s group,3
and a three-step process involving RCM/transfer hydrogenation/
hydrogenation by Grubbs.4 Many possible alternatives on this
theme can be envisioned, however, where tandem reactions might
involve metathesis either preceded or followed by a bond-forming
event that is not necessarily mediated by Ru. In this report, we
describe one such sequence leading to multiple centers of unsa-
turation in conjugation with a carbonyl activating group (Scheme
1).5 Such conjugated dienic carbonyl derivatives are common
structural subunits in natural products6 as well as useful in-
termediates in synthesis.7 Thus, there are several routes to dienone
and dienoates that rely mainly on either more modern cross-cou-
pling chemistry (e.g., the boron Heck reaction)8 or a traditional
approach (i.e., Wittig or Wittig-like)9 or both.2 On the other hand,
the combination offered by an initial olefin cross-metathesis fol-
lowed by an elimination provides novel and highly efficient inroads
to these unsaturated arrays under very mild conditions.
G
-p
]
[G = alkyl,
OR,OH, H]
[LG=O-C6 H4-NO2
1. Ru catalyst
2. base
R'
O
R
G
Scheme 1.
homoallyl alcohol, 1, was prepared anticipating that its subsequent
elimination would be facile. Other leaving groups could easily be
envisioned, but no others were tried in this study. Upon exposure of
1 to ethyl vinyl ketone (3 equiv) in refluxing CH2Cl2 (DCM) and in
the presence of 5% of the phosphine-free Grubbs–Hoveyda second
generation (GH-2) catalyst (3),11 E-enone 2 was formed in essen-
tially quantitative yield (entry 1, Table 1). The catalyst loading could
be reduced to 2% without significant change in outcome (entry 2).
Other catalysts such as 412 (entry 4) and 513 (entries 5–7) were also
screened. Both were found to be less effective under these standard
conditions, not a surprising outcome given the electron-rich tri-
cyclohexylphosphine present in each, and the reduced rates at
which these ligands dissociate from the metal center.11b Reactions
at room temperature take place, although for the allotted time
(15 h, entry 3) they were incomplete. Competing homocoupling of
the enone for reactions run at higher concentrations accounts in
part for lower yields (e.g., entry 5 vs 7).
2. Results and discussion
As an olefinic coupling partner equivalent to butadiene in
a metathesis reaction, a simple known10 ether derivative of
Butadiene equivalent 1 smoothly couples with a variety of type-
2 conjugated partners to give products 6a–6e, as illustrated in Table
2. All of the precursor enones and enoates used are commercially
available materials. Independent of their nature, elimination could
* Corresponding author.
E-mail address: lipshutz@chem.ucsb.edu (B.H. Lipshutz).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.027

6950
B.H. Lipshutz et al. / Tetrahedron 64 (2008) 6949–6954
Table 3
Synthesis of
be effected by DBU (2 equiv) in DCM at ambient temperature
within an hour at a concentration of 0.25 M. Again, conversions to
dienes 7a–7e were virtually 100% and isolated yields, likewise,
were very high. Attempts to replace DBU with Et3N were un-
successful; elimination did not occur at room temperature.
d
-substituted
a
,
b
,
g,
d
-unsaturated carbonyl derivativesa
O
3 (2 mol%)
R
CH2Cl2
Ph
O
O
2N
(2-3 equiv)
8
Table 1
O
R
DBU (2 equiv)
CH2Cl2, rt
Optimization of the CM reaction of butadiene equivalent 1a
Ph
O
O
2N
O
9
5.0% (3)
O
O
Ph
R
O
CH2Cl2 (0.2 M)
+
40 °C, 15h
10
NO2
NO2
O
Entry
R
Yield of 9b (%)
Yield of 10b (%)
"standard conditions"
1
(3 equiv)
2
1
2
3
4
5
6
7
O-t-Bu
OMe
O-2-Ethylhexyl
Me
Et
9a (93)
9b (93)
9c (96)
10a (97)
10b (92)
10c (99)
10d (99)
10e (98)
10f (88c)
10g (90)
Entry
Change from
standard conditions
Yieldb (%)
9d (95)
9e (97)
9f (75)
1
2
3
4
5
6
7
None
99
95
72
88
38
29
68
OH
H
2.0% 3 instead of 5.0% 3
2.0% 3 instead of 5.0% 3 at 22 ꢀ
5.0% 4 instead of 5.0% 3
9g (55, 96d)
C
a
Metathesis reactions were conducted at 0.2 M for 15 h at 40 ꢀC; elimination
reactions were conducted at 0.25 M for 1 h at 22 ꢀC.
5.0% 5 instead of 5.0% 3 in 0.5 M soln
5.0% 5 instead of 5.0% 3 in 0.5 M soln at 22 ꢀ
5.0% 5 instead of 5.0% 3
b
C
Isolated yield of chromatographically pure materials.
3 equiv DBU.
Based on recovered starting material.
c
d
a
Using 3 equiv ethyl vinyl ketone.
b
Isolated yield of chromatographically pure materials.
A substituted analog of 1, ether 8 (from a Mitsunobu coupling on
the corresponding commercially available alcohol precursor), also
ultimately led to a variety of conjugated carbonyl-containing
products (Table 3). In addition to the enoates and enones (entries
1–5) also examined earlier (see Table 2), both acrylic acid (2 equiv,
entry 6) and acrolein (3 equiv, entry 7) could be employed. Initial
products 9 are easily isolated and subsequently converted to doubly
unsaturated carbonyl derivatives 10 under otherwise identical
conditions as used previously (DBU, DCM, rt, 1 h). With a 1-
Mes
Mes
N
N
N Mes
N Mes
Cl2Ru
O
Cl2Ru
PCy3
3; GH-2
Mes
4
N
N Mes
substituted 3-butenol-derived ether such as 8,
-unsaturated products are to be expected (e.g., 10). Moving
the substituent to the 3-position, as in the case of 11, or what
translates into the eventual -site in the dienic product, affords
initially, e.g., -disubstituted enoate 12a or enone 12b (Scheme 2).
d-substituted
a,b,g,d
Cl2Ru
Ph
PCy3
b
5; Grubbs-2
b,b
The increased steric hindrance associated with the 1,1-di-
substituted olefin in 11 slows the metathesis reactions with both an
acrylate and an enone; additional catalyst was required (4 mol %) as
was a higher reaction concentration (0.40 M). As expected from
such metathesis reactions on 1,1-disubstituted alkenes,14 both
geometrical isomers were isolated as a roughly 1:1 mixture of E/Z
products. Elimination from the separated pure E-isomer of 12a led
to E/Z-dienoates 13a in a 5:1 E/Z ratio favoring the E-product,
suggesting that some equilibration is occurring. The pure Z-isomer
of 12a gave an inverted 1:5 ratio favoring the Z-product. Continued
Table 2
Synthesis of
a
,
b
,
g
,
d
-unsaturated carbonyl compoundsa
O
2.0% (3)
O
O
R
CH2Cl2 (0.2 M)
+
40 °C, 15 h
R
NO2
O
NO2
(enoate: 2 equiv)
(enone: 3 equiv)
1
6
R
3 (4 mol%)
O
DBU (2 equiv)
CH2Cl2,rt
+
R
CH2Cl2
O
O2N
O2N
11
O
7
O
R
DBU (2 equiv.)
CH2Cl2, rt
Entry
R
Yield of 6b (%)
Yield of 7b (%)
O
1
2
3
4
5
O-t-Bu
OMe
O-2-Ethylhexyl
Me
Et
6a (96)
6b (89)
6c (93)
6d (92)
6e (95)
7a (98)
7b (100c)
7c (99)
12
R
7d (100c)
7e (96)
O
13
a
Metathesis reactions were conducted at 0.2 M for 15 h at 40 ꢀC; elimination
R = O-t-Bu: 12a (50%); 13a (94%)
R = Et: 12b (65%); 13b (94%)
reactions were conducted at 0.25 M for 1 h at 22 ꢀC.
b
Isolated yield of chromatographically pure materials.
Conversion was measured by GC–MS.
c
Scheme 2. Synthesis of b-substituted a,b,g,d-unsaturated carbonyl compounds.

B.H. Lipshutz et al. / Tetrahedron 64 (2008) 6949–6954
6951
Table 4
4. Experimental
One-pot synthesis of conjugated diene carbonyl compoundsa
R2
4.1. General
O
O
DBU (2 equiv.)
Melting points are uncorrected. Column chromatography was
performed using Silicycle Silica-P 60 Å flash silica gel. Thin-layer-
chromatographic analysis was conducted using commercially
available EMD silica gel 60 F254 plates. Nuclear Magnetic Resonance
spectra were obtained on a Varian Inova system, in CDCl3, with
proton and carbon resonances at 400 and 100 MHz, respectively,
and are referenced to the residual solvent signal at 7.27 and
77.23 ppm, respectively. Infrared spectra were obtained either neat
or by thin film on NaCl plates using a JASCO FT/IR-430 series
spectrometer and are reported in cmꢁ1. Mass spectral data were
acquired on either a VF Autospec or an analytical VG-70-250 HF
spectrometer. Grubbs-2 and Grubbs–Hoveyda second generation
catalysts were obtained from Materia, Inc. and stored in a glove box
under an Ar atmosphere.
°
22 C, 1 h
3 (2 mol%), CH2Cl2
R1
O2N
°
40 C, 15 h
R1 = H (1)
R
1 = Ph (8)
R2
R1
O
Entry
R1, R2
Yieldb (%)
1
2
3
R1¼Ph, R2¼Et
10e (96)
10a (93)
7c (95)
R1¼Ph, R2¼O-t-Bu
R1¼H, R2¼O-2-ethylhexyl
a
Reactions were conducted at 0.2 M.
Isolated yield of chromatographically pure materials.
b
heating (90 min) at 40 ꢀC of the initial 1:1 mix of E/Z-12a did not
alter the relative amounts of dienic materials formed. Likewise,
similar treatment of each isomer for extended times ultimately
afforded the same 1:1 ratio.
4.2. 1-(But-3-enyloxy)-4-nitrobenzene (1)
To a solution of 4-nitrophenol (0.40 g, 2.88 mmol) and K2CO3
(0.99 g, 7.16 mmol) in CH3CN (20 mL) was added 4-bromo-1-bu-
tene (0.59 mL, 5.76 mmol), and the mixture was refluxed for 18 h.
The solution was filtered through Celite and the filtrate concen-
trated under reduced pressure. The residue was dissolved in CH2Cl2,
washed with water, dried, and the solvent was removed under
reduced pressure to give a yellow residue, which was chromato-
graphed (hexanes–ethyl acetate, 24:1) to give 1 (0.55 g, 99%) as
a pale yellow liquid. The spectroscopic data obtained for the
product was in accord with that previously reported for this
compound.10
The potential for both the cross-metathesis and the elimination
steps to be carried out in a tandem, one-pot sequence was dem-
onstrated with educts 1 and 8 (Table 4). Thus, following initial
metathesis to either an enone (with 8, entry 1) or an enoate (with 8,
entry 2; with 1, entry 3), introduction of DBU to the mixture at
room temperature led smoothly to the desired doubly unsaturated
products 10e, 10a, and 7c in high overall isolated yields.
Lastly, we have recently reported that the amphiphile ‘PTS’
(14),15 present only to the extent of ca. 2.5% (by weight), allows for
cross-metathesis within nanometer micelles in pure water.16
Hence, application of this ‘green’ chemistry to the one-pot process
at hand leads from olefin 1 and tert-butyl acrylate to dienoate 7a in
high overall yield (Scheme 3).
4.3. 1-Nitro-4-(1-phenylbut-3-enyloxy)benzene (8)
Preparation of 8 follows from a known procedure,17 using 4-
nitrophenol (1.07 g, 7.70 mmol), 1-phenylbut-3-en-1-ol (1.04 g,
7.00 mmol), triphenylphosphine (2.02 g, 7.70 mmol), and di-(4-
chlorobenzyl)azodicarboxylate (2.95 g, 8.05 mmol). Column chro-
matography (eluting with 10% EtOAc/hexanes) afforded the product
as a pale yellow liquid (1.41 g, 75%); IR (neat): 3081, 3032, 2979,
2913, 2844, 1642, 1593, 1510, 1454, 1342, 1298, 1253, 1173, 1112,
O
O
3 (2 mol%), 15 h
,
1)
O
O
2.5% PTS/H2O, 40 °C
O
NO2
2) DBU (2 equiv.), rt, 1 h
7a (93%)
1
1078, 1002, 921, 860, 845 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d 8.10
Scheme 3. Cross-metathesis/elimination in PTS/H2O.
O
O
O
O
H
n
4
O
O
14 (PTS; n = ca. 13)
3. Conclusions
(d, J¼9.2 Hz, 2H), 7.38–7.28 (m, 5H), 6.90 (d, J¼9.2 Hz, 2H), 5.89–
5.78 (m, 1H), 5.24 (dd, J¼7.6, 5.6 Hz, 1H), 5.17–5.10 (m, 2H), 2.84–
Homoallylic alcohols derivatized as their p-nitrophenol de-
rivatives readily participate in olefin cross-metathesis reactions,
both in traditional methylene chloride solution and in neat water
using a small percentage of the nonionic surfactant PTS. The
resulting initial products, which are activated carbonyl derivatives
and can be isolated, have been shown to subsequently undergo
elimination at room temperature under the influence of DBU
to form doubly unsaturated derivatives. This new two-step se-
quence can also be effected in a single pot operation in high overall
yields.
2.77 (m, 1H), 2.68–2.61 (m,1H); 13C NMR (100 MHz, CDCl3):
d 163.2,
141.4, 139.9, 133.4, 128.9, 128.3, 126.0, 125.8, 118.4, 115.9, 80.7, 42.8;
MS (ESI): m/z 292 (MþNa); HRMS (ESI) calcd for C16H15NO3Na
[MþNa]þ¼292.0950, found 292.0943.
4.4. 1-(3-Methylbut-3-enyloxy)-4-nitrobenzene (11)
Preparation of 11 was achieved according to a known pro-
cedure,17 using 4-nitrophenol (1.07 g, 7.70 mmol), 3-methylbut-3-
en-1-ol (0.71 mL, 7.00 mmol), triphenylphosphine (2.02 g,

6952
B.H. Lipshutz et al. / Tetrahedron 64 (2008) 6949–6954
7.70 mmol), and di-(4-chlorobenzyl)azodicarboxylate (2.95 g,
8.05 mmol). Column chromatography (eluting with 5% EtOAc/
hexanes) afforded the product as a yellow liquid (1.28 g, 88%); IR
(neat): 3081, 2939, 1651, 1595, 1518, 1471, 1377, 1347, 1299, 1260,
3033, 2959, 2930, 2860, 1719, 1659, 1606, 1593, 1514, 1495, 1455,
1380,1342,1253,1198,1171,1112,1021, 978, 875, 847 cmꢁ1; 1H NMR
(400 MHz, CDCl3):
d
8.20 (d, J¼9.2 Hz, 2H), 7.00 (dt, J¼15.6, 6.8 Hz,
1H), 6.95 (d, J¼9.2 Hz, 2H), 5.98 (d, J¼15.6 Hz, 1H), 4.17 (t, J¼6.4 Hz,
2H), 4.07 (dd, J¼10.8, 5.6 Hz,1H), 4.04 (dd, J¼10.8, 6.0 Hz,1H), 2.76–
2.71 (m, 2H), 1.63–1.59 (m, 1H), 1.38–1.28 (m, 8H), 0.91–0.88 (m,
1173, 1111, 1039, 1012, 896, 846 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
d
8.20 (d, J¼9.2 Hz, 2H), 6.96 (d, J¼9.2 Hz, 2H), 4.88 (d, J¼1.2 Hz,1H),
4.81 (d, J¼1.2 Hz, 1H), 4.18 (t, J¼6.8 Hz, 2H), 2.55 (t, J¼6.8 Hz, 2H),
1.82 (s, 3H); 13C NMR (100 MHz, CDCl3):
164.2, 142.0, 126.1, 114.6,
6H); 13C NMR (100 MHz, CDCl3):
d
166.6, 163.7, 143.6, 141.8, 126.1,
d
124.2, 114.6, 67.1, 66.9, 38.9, 31.9, 30.6, 29.1, 24.0, 23.1, 14.2, 11.2; MS
112.7, 67.4, 37.0, 22.9; MS (EI) m/z (%): 207 (M, 7), 179 (5), 152 (4), 69
(100); HRMS (EI) calcd for C11H13NO3 [M]þ¼207.0895, found
207.0903.
(ESI): m/z 372 (MþNa); HRMS (ESI) calcd for
[MþNa]þ¼372.1787, found 372.1792.
C19H27NO5Na
4.5.4. (E)-6-(4-Nitrophenoxy)hex-3-en-2-one (6d)
4.5. General procedure for cross-metathesis
From olefin 1 (97 mg, 0.50 mmol) following the general pro-
cedure using methylvinyl ketone (122 L,1.50 mmol), and catalyst 3
m
The general procedure is illustrated by the preparation of
dienone 9e. To a solution of olefin 8 (135 mg, 0.50 mmol) and ethyl
vinyl ketone (149 mL, 1.5 mmol) in CH2Cl2 (2.5 mL) was added 3
(6.3 mg, 0.01 mmol, 2.0 mol %), and the mixture was refluxed for
15 h. The flask was fitted with a condenser and refluxed under ar-
gon for 15 h. The reaction mixture was then reduced in volume to
0.5 mL and purified directly on a silica gel column, eluting with 6:1
hexanes–ethyl acetate to provide 9e (158 mg, 97%) as a pale yellow
liquid. IR (neat): 3085, 3033, 2978, 2938, 1699, 1674, 1632, 1592,
(6.3 mg, 0.01 mmol), elution with 4:1 hexanes–ethyl acetate affor-
ded 6d (108 mg, 92%) as a white solid. Mp¼56–57 ꢀC; IR (thin film):
3079, 3023, 2952, 1699, 1678, 1631, 1594, 1501, 1426, 1337, 1271,
1210, 1179, 1112, 1020, 990, 858, 818 cmꢁ1 1H NMR (400 MHz,
;
CDCl3):
d
8.23 (d, J¼9.2 Hz, 2H), 6.98 (d, J¼9.2 Hz, 2H), 6.87 (dt,
J¼16.0, 6.8 Hz, 1H), 6.23 (dt, J¼16.0, 1.6 Hz, 1H), 4.20 (t, J¼6.4 Hz,
2H), 2.78 (qd, J¼6.0, 1.2 Hz, 2H), 2.29 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 198.4,163.7,142.8,141.8,133.5,126.1,114.6, 66.8, 32.1, 27.3;
MS (ESI): m/z 258 (MþNa), 236 (MþH); HRMS (ESI) calcd for
1510, 1455, 1419, 1342, 1253, 1200, 1173, 1112, 979, 917, 847 cmꢁ1
1H NMR (400 MHz, CDCl3):
;
C
12H13NO4Na [MþNa]þ¼258.0742, found 258.0738.
d
8.07 (d, J¼9.2 Hz, 2H), 7.38–7.27 (m,
5H), 6.89 (d, J¼9.2 Hz, 2H), 6.83 (dt, J¼16.0, 7.2 Hz, 1H), 6.17 (d,
J¼16.0 Hz, 1H), 5.34 (dd, J¼7.6, 4.8 Hz, 1H), 2.97–2.89 (m, 1H), 2.83–
2.76 (m, 1H), 2.54 (q, J¼7.2 Hz, 2H), 1.07 (t, J¼7.2 Hz, 3H); 13C NMR
4.5.5. (E)-7-(4-Nitrophenoxy)hept-4-en-3-one (6e)
From olefin 1 (97 mg, 0.50 mmol) following the general pro-
cedure using ethyl vinyl ketone (150 mL, 1.50 mmol) and catalyst 3
(100 MHz, CDCl3):
d
200.8, 162.8, 141.7, 140.6, 139.3, 132.9, 129.2,
(6.3 mg, 0.01 mmol), elution with 4:1 hexanes–ethyl acetate,
afforded 6e (119 mg, 95%) as a white solid. Mp¼44–46 ꢀC; IR (thin
film): 3086, 2977, 2938, 1698, 1673, 1633, 1607, 1593, 1512, 1469,
128.7, 125.9, 125.8, 115.9, 79.7, 41.4, 33.7, 8.1; MS (ESI): m/z 364
(MþK), 348 (MþNa), 326 (MþH); HRMS (ESI) calcd for
C
19H19NO4Na [MþNa]þ¼348.1212, found 348.1209.
1341, 1299, 1262, 1174, 1111, 1025, 978, 847 cmꢁ1 1H NMR
;
(400 MHz, CDCl3):
d
8.22 (d, J¼9.2 Hz, 2H), 6.96 (d, J¼9.2 Hz, 2H),
4.5.1. (E)-tert-Butyl 5-(4-nitrophenoxy)pent-2-enoate (6a)
6.89 (dt, J¼16.0, 7.2 Hz, 1H), 6.26 (dt, J¼16.0, 1.2 Hz, 1H), 4.19 (t,
J¼6.4 Hz, 2H), 2.76 (qd, J¼6.4, 1.2 Hz, 2H), 2.61 (q, J¼7.2 Hz, 2H), 1.12
From olefin 1 (97 mg, 0.50 mmol) following the general pro-
cedure using tert-butyl acrylate (146
m
L, 1.0 mmol) and catalyst 3
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 200.9, 163.7, 141.8,
(6.3 mg, 0.01 mmol), elution with 19:1 hexanes–ethyl acetate,
afforded 6a (141 mg, 96%) as a colorless liquid. IR (neat): 3115, 3087,
2979, 2934, 1709, 1656, 1595, 1509, 1473, 1391, 1367, 1340, 1265,
141.4, 132.3, 126.1, 114.6, 66.9, 33.7, 32.1, 8.1; MS (CI) m/z (%): 250
(MþH, 15), 178 (11), 140 (55), 111 (100); HRMS (CI) calcd for
C
13H16NO4 [MþH]þ¼250.1079, found 250.1083.
1173, 1111, 1029, 981, 848 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 8.21
(d, J¼9.2 Hz, 2H), 6.96 (d, J¼9.2 Hz, 2H), 6.91 (dt, J¼15.6, 6.8 Hz, 1H),
4.5.6. (E)-tert-Butyl 5-(4-nitrophenoxy)-5-phenylpent-
2-enoate (9a)
5.90 (d, J¼15.6 Hz, 1H), 4.17 (t, J¼6.4 Hz, 2H), 2.72 (qd, J¼6.8, 1.6 Hz,
2H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
165.7, 163.8, 142.4,
From olefin 8 (135 mg, 0.50 mmol) following the general pro-
141.8, 126.1, 125.8, 114.6, 80.7, 67.0, 31.7, 28.3; MS (ESI): m/z 316
cedure using tert-butyl acrylate (146 mL, 1.00 mmol) and catalyst 3
(MþNa), 294 (MþH); HRMS (ESI) calcd for
C
15H19NO5Na
(6.3 mg, 0.01 mmol), elution with 19:1 hexanes–ethyl acetate,
afforded 9a (172 mg, 93%) as a colorless liquid. IR (neat): 3063,
2979, 2932, 1711, 1656, 1593, 1513, 1495, 1455, 1422, 1391, 1367,
1342, 1253, 1152, 1112,1009, 981, 917, 847 cmꢁ1; 1H NMR (400 MHz,
[MþNa]þ¼316.1161, found 316.1161.
4.5.2. (E)-Methyl 5-(4-nitrophenoxy)pent-2-enoate (6b)
From olefin 1 (124 mg, 0.64 mmol) following the general pro-
cedure using methyl acrylate (173 L, 1.92 mmol) and catalyst 3
CDCl3):
d
8.08 (d, J¼9.2 Hz, 2H), 7.38–7.28 (m, 5H), 6.91–6.85 (m,
m
3H), 5.85 (d, J¼15.6 Hz, 1H), 5.31 (dd, J¼7.6, 4.8 Hz, 1H), 2.94–2.86
(8.0 mg, 0.013 mmol), elution with 9:1 hexanes–ethyl acetate,
afforded 6b (143 mg, 89%) as a white solid. Mp¼41–43 ꢀC; IR (thin
film): 3114, 3086, 2951, 1722, 1660, 1607, 1594, 1512, 1469, 1437,
(m, 1H), 2.78–2.73 (m, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
165.7, 162.9, 142.0, 141.7, 139.5, 129.2, 128.6, 126.3, 125.9, 116.0,
80.7, 79.7, 41.1, 28.3; MS (ESI): m/z 408 (MþK), 392 (MþNa), 370
(MþH); HRMS (ESI) calcd for C21H23NO5Na [MþNa]þ¼392.1474,
found 392.1467.
1342, 1299, 1262, 1219, 1173, 1111, 1031, 978, 847 cmꢁ1 1H NMR
;
(400 MHz, CDCl3):
d
8.22 (d, J¼9.2 Hz, 2H), 7.04 (dt, J¼16.0, 6.8 Hz,
1H), 6.96 (d, J¼9.2 Hz, 2H), 6.00 (dt, J¼16.0, 1.2 Hz, 1H), 4.18 (t,
J¼6.4 Hz, 2H), 3.76 (s, 3H), 2.75 (qd, J¼6.4, 1.2 Hz, 2H); 13C NMR
4.5.7. (E)-Methyl 5-(4-nitrophenoxy)-5-phenylpent-2-enoate (9b)
From olefin 8 (108 mg, 0.40 mmol) following the general pro-
(100 MHz, CDCl3):
d 166.8, 163.7, 144.2, 141.9, 126.1, 123.7, 114.6,
66.8, 51.8, 31.9; MS (ESI): m/z 274 (MþNa), 252 (MþH); HRMS (ESI)
cedure using methyl acrylate (108 mL, 1.20 mmol) and catalyst 3
calcd for C12H13NO5Na [MþNa]þ¼274.0691, found 274.0696.
(5.0 mg, 0.008 mmol), elution with 7:1 hexanes–ethyl acetate,
afforded 9b (122 mg, 93%) as a pale yellow liquid. IR (neat): 3084,
3031, 2951, 2844, 1721, 1660, 1593, 1513, 1495, 1454, 1436, 1342,
4.5.3. (E)-2-Ethylhexyl 5-(4-nitrophenoxy)pent-2-enoate (6c)
From olefin 1 (97 mg, 0.50 mmol) following the general pro-
1251, 1201, 1172, 1112, 1023, 979, 917, 862, 847 cmꢁ1 1H NMR
;
cedure using O-2-ethylhexyl acrylate (209
mL, 1.0 mmol) and cata-
(400 MHz, CDCl3): d 8.10–8.06 (m, 2H), 7.37–7.29 (m, 5H), 6.99 (dt,
lyst 3 (6.3 mg, 0.01 mmol), elution with 11:1 hexanes–ethyl acetate,
afforded 6c (163 mg, 93%) as a pale yellow liquid. IR (neat): 3064,
J¼15.6, 7.2 Hz, 1H), 6.91–6.87 (m, 2H), 5.92 (d, J¼15.6 Hz, 1H), 5.34
(dd, J¼7.2, 4.4 Hz, 1H), 3.71 (s, 3H), 2.96–2.89 (m, 1H), 2.82–2.76 (m,

B.H. Lipshutz et al. / Tetrahedron 64 (2008) 6949–6954
6953
1H); 13C NMR (100 MHz, CDCl3):
129.2, 128.6, 125.9, 125.8, 124.2, 115.9, 79.5, 51.7, 41.2; MS (ESI): m/z
350 (MþNa); HRMS (ESI) calcd for C18H17NO5Na [MþNa]þ¼
350.1004, found 350.1010.
d
166.6, 162.8, 143.5, 141.7, 139.3,
139.0, 135.6, 129.4, 128.9, 126.0, 125.8, 116.0, 79.3, 41.5; MS (ESI):
m/z 320 (MþNa); HRMS (ESI) calcd for C17H15NO4Na [MþNa]þ¼
320.0899, found 320.0900.
4.5.12. tert-Butyl-3-methyl-5-(4-nitrophenoxy)pent-
2-enoate (12a)
4.5.8. (E)-2-Ethylhexyl 5-(4-nitrophenoxy)-5-phenylpent-
2-enoate (9c)
From olefin 11 (165 mg, 0.80 mmol) following the general pro-
From olefin 8 (108 mg, 0.40 mmol) following the general pro-
cedure using tert-butyl acrylate (58 mL, 0.40 mmol) and catalyst 3
cedure using O-2-ethylhexyl acrylate (167
m
L, 0.80 mmol) and cat-
(10.0 mg, 0.016 mmol), elution with 13:1 hexanes–ethyl acetate,
afforded 12a (61 mg, 50%, E/Z¼1:1) as a pale yellow liquid. The E/Z
ratios were determined by relative integrations of the vinylic
methyl resonances at 2.21 and 1.99 ppm. (E)-Isomer. Rf¼0.55 (4:1
hexanes–ethyl acetate); IR (neat): 3114, 3087, 2978, 1712, 1651,
alyst 3 (5.0 mg, 0.008 mmol), elution with 11:1 hexanes–ethyl
acetate, afforded 9c (164 mg, 96%) as a pale yellow liquid. IR (neat):
3064, 3033, 2959, 2930, 2860, 1719, 1658, 1601, 1593, 1516, 1495,
1455, 1380, 1342, 1253, 1198, 1171, 1112, 1021, 980, 862, 846 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
8.08 (d, J¼9.2 Hz, 2H), 7.38–7.28 (m,
1593, 1516, 1390, 1342, 1299, 1259, 1173, 1142, 1111, 1032, 847 cmꢁ1
1H NMR (400 MHz, CDCl3):
;
5H), 6.97 (dt, J¼15.6, 7.2 Hz, 1H), 6.89 (d, J¼9.2 Hz, 2H), 5.93 (dt,
J¼15.6, 1.2 Hz, 1H), 5.33 (dd, J¼7.6, 4.8 Hz, 1H), 4.06 (dd, J¼10.8,
6.0 Hz, 1H), 4.03 (dd, J¼10.8, 6.0 Hz, 1H), 2.97–2.89 (m, 1H), 2.83–
2.76 (m, 1H), 1.62–1.56 (m, 1H), 1.39–1.32 (m, 2H), 1.28 (br s, 6H),
d
8.20 (d, J¼9.6 Hz, 2H), 6.95 (d,
J¼9.6 Hz, 2H), 5.69 (q, J¼1.2 Hz, 1H), 4.19 (t, J¼6.8 Hz, 2H), 2.63 (t,
J¼6.8 Hz, 2H), 2.21 (d, J¼1.2 Hz, 3H), 1.48 (s, 9H); 13C NMR
(100 MHz, CDCl3):
d 166.1, 163.8, 153.0, 141.8, 126.1, 120.0, 114.6,
0.91–0.87 (m, 6H); 13C NMR (100 MHz, CDCl3):
d
166.4, 162.8, 143.0,
80.2, 66.6, 39.9, 28.4, 18.9; MS (CI) m/z (%): 308 (MþH, 3), 252 (21),
234 (100), 113 (30), 95 (12); HRMS (CI) calcd for C16H22NO5
[MþH]þ¼308.1498, found 308.1493. (Z)-Isomer. Rf¼0.61 (4:1 hex-
anes–ethyl acetate); IR (neat): 3114, 3087, 2978, 2934, 1708, 1649,
1595, 1510,1470,1366,1333,1253,1174,1142,1112,1086,1052,1032,
141.7, 139.3, 129.2, 128.6, 125.9, 124.7, 115.9, 79.6, 67.0, 41.2, 38.9,
30.5, 29.0, 23.9, 23.1, 14.2, 11.2; MS (ESI): m/z 464 (MþK), 448
(MþNa), 426 (MþH); HRMS (ESI) calcd for
C25H31NO5Na
[MþNa]þ¼448.2100, found 448.2113.
1011, 901, 847 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
8.19 (d, J¼9.2 Hz,
4.5.9. (E)-6-(4-Nitrophenoxy)-6-phenylhex-3-en-2-one (9d)
From olefin 8 (108 mg, 0.40 mmol) following the general pro-
2H), 6.98 (d, J¼9.2 Hz, 2H), 5.74 (q, J¼1.2 Hz, 1H), 4.24 (t, J¼6.8 Hz,
2H), 3.09 (t, J¼6.8 Hz, 2H), 1.99 (d, J¼1.2 Hz, 3H), 1.47 (s, 9H); 13C
cedure using methylvinyl ketone (97
mL, 1.20 mmol) and catalyst 3
NMR (100 MHz, CDCl3): d 165.8, 164.1, 154.1, 141.6, 126.1, 120.4,
(5.0 mg, 0.008 mmol), elution with 4:1 hexanes–ethyl acetate,
afforded 9d (119 mg, 95%) as a white solid. Mp¼95–97 ꢀC; IR (thin
film): 3084, 3033, 2923, 1698, 1676, 1630, 1593, 1509, 1454, 1423,
114.7, 80.2, 67.8, 33.0, 28.4, 26.5; MS (CI) m/z (%): 308 (MþH, 26),
252 (71), 234 (25), 169 (11), 113 (100); HRMS (CI) calcd for
C
16H22NO5 [MþH]þ¼308.1498, found 308.1489.
1341, 1298, 1252, 1173, 1112, 980, 918 cmꢁ1 1H NMR (400 MHz,
;
CDCl3):
d
8.06 (d, J¼9.2 Hz, 2H), 7.37–7.27 (m, 5H), 6.88 (d, J¼9.2 Hz,
4.5.13. 5-Methyl-7-(4-nitrophenoxy)hept-4-en-3-one (12b)
From olefin 11 (207 mg, 1.00 mmol) following the general pro-
cedure using ethyl vinyl ketone (50 mL, 0.50 mmol) and catalyst 3
(12.6 mg, 0.02 mmol), elution with 8:1 hexanes–ethyl acetate,
afforded 12b (85 mg, 65%, E/Z¼5:4) as a pale yellow liquid. The E/Z
ratios were determined by relative integrations of the vinylic
methyl resonances at 2.22 and 2.02 ppm. (E)-Isomer. Rf¼0.50 (3:1
hexanes–ethyl acetate); IR (neat): 2937, 1688, 1625, 1608, 1593,
2H), 6.80 (dt, J¼16.0, 7.2 Hz, 1H), 6.14 (d, J¼16.0 Hz, 1H), 5.36 (dd,
J¼7.6, 4.8 Hz,1H), 2.97–2.90 (m,1H), 2.84–2.75 (m,1H), 2.22 (s, 3H);
13C NMR (100 MHz, CDCl3):
d
198.3, 162.7, 142.0, 141.6, 139.2, 134.0,
129.2, 128.6, 125.8, 125.8, 115.9, 79.5, 41.3, 27.2; MS (ESI): m/z 334
(MþNa); HRMS (ESI) calcd for C18H17NO4Na [MþNa]þ¼334.1055,
found 334.1056.
4.5.10. (E)-5-(4-Nitrophenoxy)-5-phenylpent-2-enoic acid (9f)
From olefin 8 (108 mg, 0.40 mmol) following the general pro-
cedure using acrylic acid (55
0.008 mmol), elution with 4:1 hexanes–ethyl acetate, afforded 9f
(94 mg, 75%) as a white solid. Mp¼38–41 ꢀC; IR (thin film): 3032,
2917, 1697, 1653, 1607, 1593, 1514, 1495, 1454, 1422, 1342, 1298,
1253, 1173, 1112, 1011, 980, 911, 863, 846 cmꢁ1; 1H NMR (400 MHz,
1513, 1471, 1341, 1299, 1261, 1173, 1111, 1030, 847 cmꢁ1
(400 MHz, CDCl3):
;
1H NMR
d
8.20 (d, J¼9.2 Hz, 2H), 6.95 (d, J¼9.2 Hz, 2H),
mL, 0.80 mmol) and catalyst 3 (5.0 mg,
6.16 (s, 1H), 4.21 (t, J¼6.4 Hz, 2H), 2.65 (t, J¼6.4 Hz, 2H), 2.48 (q,
J¼7.6 Hz, 2H), 2.22 (s, 3H),1.08 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 201.7, 163.8,152.6,141.8, 126.1,125.3,114.6, 66.5, 40.2, 37.7,
19.5, 8.2; MS (EI) m/z (%): 263 (M, 6), 245 (10), 234 (100), 152 (36),
125 (24), 124 (48), 95 (47), 57 (47); HRMS (EI) calcd for C14H17NO4
[M]þ¼263.1158, found 263.1161. (Z)-Isomer. Rf¼0.62 (3:1 hexanes–
CDCl3):
d
8.09 (d, J¼9.2 Hz, 2H), 7.39–7.29 (m, 5H), 7.11 (dt, J¼15.6,
7.2 Hz, 1H), 6.89 (d, J¼9.2 Hz, 2H), 5.93 (d, J¼15.6 Hz, 1H), 5.36 (dd,
ethyl acetate); 1H NMR (400 MHz, CDCl3):
d
8.18 (d, J¼9.2 Hz, 2H),
J¼7.6, 4.8 Hz, 1H), 3.00–2.92 (m, 1H), 2.87–2.80 (m, 1H); 13C NMR
6.97 (d, J¼9.2 Hz, 2H), 6.21 (s, 1H), 4.24 (t, J¼6.4 Hz, 2H), 3.04 (t,
(100 MHz, CDCl3):
d 171.7, 162.7, 146.2, 141.8, 139.1, 129.3, 128.8,
J¼6.4 Hz, 2H), 2.47 (q, J¼7.2 Hz, 2H), 2.02 (s, 3H), 1.07 (t, J¼7.2 Hz,
125.9, 125.8, 124.0, 116.0, 79.4, 41.2; MS (ESI): m/z 336 (MþNa);
HRMS (ESI) calcd for C17H15NO5Na [MþNa]þ¼336.0848, found
336.0853.
3H); 13C NMR (100 MHz, CDCl3):
d 201.4, 164.1, 154.5, 141.6, 126.1,
125.4, 114.7, 68.0, 37.6, 33.8, 27.1, 8.1; HRMS (EI) calcd for C14H17NO4
[M]þ¼263.1158, found 263.1149.
4.5.11. (E)-5-(4-Nitrophenoxy)-5-phenylpent-2-enal (9g)
4.6. General procedure for the preparation of doubly
unsaturated carbonyl derivatives
From olefin 8 (108 mg, 0.40 mmol) following the general pro-
cedure using acrolein (80 mL, 1.20 mmol) and catalyst 3 (5.0 mg,
0.008 mmol), elution with 4:1 hexanes–ethyl acetate, afforded 9g
(65 mg, 55%, 96% based on recovered starting material) as a color-
less liquid. IR (neat): 3112, 3084, 3033, 2918, 2828, 2739,1686,1638,
1607,1593,1509, 1493, 1454,1422, 1342,1298,1251,1173,1133,1113,
The general procedure is illustrated by the preparation of 10c.
DBU (0.10 mL, 0.68 mmol) was added dropwise to a solution of 9c
(145 mg, 0.34 mmol) in CH2Cl2 (1.4 mL) and the reaction mixture
was stirred at 22 ꢀC for 1 h. HCl (3 mL, 1.0 M) was added and the
mixture was extracted with CH2Cl2. The combined organic layers
were washed with water, dried, and the solvent was removed un-
der reduced pressure to give a light yellow residue, which was
chromatographed (hexanes–ethyl acetate, 20:1) to give 10c (97 mg,
99%) as a colorless liquid. IR (neat): 3060, 3028, 2959, 2860, 1710,
1004, 975, 917, 862, 847 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 9.52 (d,
J¼8.0 Hz, 1H), 8.09 (d, J¼9.2 Hz, 2H), 7.40–7.30 (m, 5H), 6.90 (d,
J¼9.2 Hz, 2H), 6.78 (dt, J¼15.6, 7.2 Hz, 1H), 6.20 (ddt, J¼15.6, 8.0,
1.2 Hz, 1H), 5.40 (dd, J¼7.6, 4.4 Hz, 1H), 3.10–3.02 (m, 1H), 2.97–2.90
(m, 1H); 13C NMR (100 MHz, CDCl3):
d 193.7, 162.6, 152.1, 141.9,

6954
B.H. Lipshutz et al. / Tetrahedron 64 (2008) 6949–6954
1627, 1461, 1382, 1343, 1237, 1173, 1132, 999, 947, 916, 878,
838 cmꢁ1 1H NMR (400 MHz, CDCl3):
7.48–7.40 (m, 3H), 7.38–
7.30 (m, 3H), 6.93–6.84 (m, 2H), 6.01 (d, J¼15.6 Hz, 1H), 4.11 (dd,
J¼10.8, 6.0 Hz, 1H), 4.08 (dd, J¼10.8, 6.0 Hz, 1H), 1.67–1.61 (m, 1H),
1.43–1.32 (m, 8H), 0.94–0.90 (m, 6H); 13C NMR (100 MHz, CDCl3):
homogeneous reaction mixture was then diluted with EtOAc
(5 mL), filtered through a bed of silica gel layered over Celite, and
the bed washed (3ꢂ10 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 5.0%
EtOAc/hexanes) to yield 7a as a white solid (29 mg, 93%).
;
d
d
167.4, 144.6, 140.5, 136.2, 129.2, 129.0, 127.3, 126.4, 121.6, 67.0,
39.0, 30.6, 29.1, 24.0, 23.2,14.3,11.2; MS (EI) m/z (%): 286 (M,12),174
(48), 157 (29), 129 (100), 128 (40); HRMS (EI) calcd for C19H26O2
[M]þ¼286.1933, found 286.1927.
Acknowledgements
Financial support provided by Zymes, LLC is warmly acknowl-
edged with thanks. Catalysts were generously provided by Materia,
for which we are most grateful.
4.6.1. (E)-2-Ethylhexyl penta-2,4-dienoate (7c)
From enoate 6c (18.6 mg, 0.053 mmol) following the general
procedure using DBU (16 mL, 0.11 mmol), elution with 20:1 hex-
anes–ethyl acetate, afforded 7c (11 mg, 99%) as a colorless liquid. IR
(neat): 3091, 2960, 2861, 1717, 1643, 1601, 1463, 1417, 1381, 1305,
1265, 1200, 1143, 1009, 922, 868 cmꢁ1; 1H NMR (400 MHz, CDCl3):
References and notes
d
7.25 (dd, J¼15.6, 10.8 Hz,1H), 6.46 (dt, J¼18.0, 10.0 Hz,1H), 5.92 (d,
1. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450; (b) Furstner, 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. 2006, 45, 6086–
6101; (j) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45–52.
2. (a) Murelli, R. P.; Snapper, M. L. Org. Lett. 2007, 9, 1749–1752, and references
therein; (b) Paul, T.; Andrade, R. B. Tetrahedron Lett. 2007, 48, 5367–5370.
3. Beligny, S.; Eibauer, S.; Maechling, S.; Blechert, S. Angew. Chem., Int. Ed. 2006, 45,
1900–1903.
J¼15.6 Hz, 1H), 5.61 (d, J¼16.8 Hz, 1H), 5.49 (d, J¼10.4 Hz, 1H), 4.08
(dd, J¼11.2, 6.0 Hz, 1H), 4.05 (dd, J¼11.2, 6.0 Hz, 1H), 1.61–1.59 (m,
1H), 1.42–1.29 (m, 8H), 0.92–0.88 (m, 6H); 13C NMR (100 MHz,
CDCl3):
d 167.3, 144.7, 135.0, 125.7, 122.5, 67.1, 39.0, 30.6, 29.1, 24.0,
23.2, 14.3, 11.2; MS (CI) m/z (%): 211 (MþH, 80), 113 (35), 99 (95), 81
(100), 71 (39), 57 (48); HRMS (CI) calcd for
C13H23O2
[MþH]þ¼211.1698, found 211.1695.
4.6.2. 5-Methylhepta-4,6-dien-3-one (13b)
4. Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312–11313.
5. For a related approach that generates the a,b-unsaturation of a dienic ester en
route to an intermediate for the synthesis of elaiolide, see Morita, A.; Kuwahara,
S. Tetrahedron Lett. 2007, 48, 3163–3166.
From enone 12b (21 mg, 0.08 mmol) following the general
procedure using DBU (24 L, 0.16 mmol), elution with 13:1 hex-
m
anes–ethyl acetate, afforded 13b (9.3 mg, 94%, E/Z¼3.4:1) as a col-
6. (a) Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466–
468; (b) Trost, B. M.; Wrobleski, S. T.; Chisholm, J. D.; Harrington, P. E.; Jung, M.
J. Am. Chem. Soc. 2005, 127, 13589–13597; (c) Schreiber, S. L.; Satake, K. J. Am.
Chem. Soc. 1984, 106, 4186–4188; (d) Glasby, J. S. Encyclopaedia of the Terpenoids;
Wiley: Chichester, UK, 1982; (e) Devon, T. K.; Scott, A. I. Handbook of Naturally
Occurring Compounds; Academic: New York, NY, 1972; Vol. II; (f) DellaGreca, M.;
Marino, C. D.; Zarrelli, A.; D’Abrosca, B. J. Nat. Prod. 2004, 67, 1492–1495; (g) Lv,
F.; Deng, Z.; Li, J.; Fu, H.; Van Soest, R. W. M.; Proksch, P.; Lin, W. J. Nat. Prod.
2004, 67, 2033–2036; (h) Cheng, Y.; Schneider, B.; Riese, U.; Schubert, B.; Li, Z.;
Hamburger, M. J. Nat. Prod. 2004, 67, 1854–1858; (i) Rogers, E. W.; Molinski, T. F.
J. Nat. Prod. 2005, 68, 450–452; (j) Mohamad, H.; Lajis, N. H.; Abas, F.; Ali, A. M.;
Sukari, M. A.; Kikuzaki, H.; Nakatani, N. J. Nat. Prod. 2005, 68, 285–288; (k)
Maskey, R. P.; Gru¨n-Wollny, I.; Laatsch, H. J. Nat. Prod. 2005, 68, 865–870.
7. (a) Luh, T.-Y.; Wong, K.-T. Synthesis 1993, 349–370; (b) Vanderwal, C. D.; Vos-
burg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393–5407; (c)
Trost, B. M.; Pinkerton, A. B.; Seidel, M. J. Am. Chem. Soc. 2001, 123, 12466–
12476; (d) Juhl, M.; Monrad, R.; Søtofte, I.; Tanner, D. J. Org. Chem. 2007, 72,
4644–4654; (e) Tatsuta, K.; Yamaguchi, T.; Tsuda, Y.; Yamaguchi, Y.; Hattori, N.;
Nagai, H.; Hosokawa, S. Tetrahedron Lett. 2007, 48, 4187–4190.
8. (a) Yoo, K. S.; Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384–16393;
(b) Yoon, C. H.; Yoo, K. S.; Yi, S. W.; Mishra, R. K.; Jung, K. W. Org. Lett. 2004, 6,
4037–4039; (c) Keck, D.; Muller, T.; Bra¨se, S. Synlett 2006, 3457–3460; (d)
Hamada, T.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999, 121, 7342–7344.
9. (a) Herra´n, G. D. L.; Murcia, C.; Csa´ky¨, A. G. Org. Lett. 2005, 7, 5629–5632; (b)
Kim, H.-O.; Ogbu, C. O.; Nelson, S.; Kahn, M. Synlett 1998, 1059–1060; (c) Jeges,
G.; Skoda-Fo¨ldes, R.; Kolla´r, L.; Horva´th, J.; Tuba, Z. Tetrahedron 1998, 54, 6767–
6780.
orless liquid. The E/Z ratios were determined by relative
integrations of the
(neat): 2925, 1686, 1593, 1459, 1377, 1241, 1127, 1035, 920,
865 cmꢁ1 1H NMR (400 MHz, CDCl3):
g-methine resonances at 6.37 and 7.74 ppm. IR
;
d
for cis: 7.74 (dd, J¼17.6,
10.8 Hz, 1H), 6.07 (s, 1H), 5.62 (d, J¼17.6 Hz, 1H), 5.45 (d, J¼10.8 Hz,
1H), 2.48 (q, J¼7.2 Hz, 2H), 1.99 (d, J¼1.2 Hz, 3H), 1.08 (t, J¼7.2 Hz,
3H); for trans: 6.37 (dd, J¼17.6, 10.8 Hz, 1H), 6.14 (s, 1H), 5.66 (d,
J¼17.6 Hz, 1H), 5.44 (d, J¼10.8 Hz, 1H), 2.51 (q, J¼7.2 Hz, 2H), 2.24
(d, J¼1.2 Hz, 3H), 1.09 (t, J¼7.2 Hz, 3H)]; MS (EI) m/z (%): 124 (M, 25),
109 (11), 95 (100), 67 (78).
4.7. General procedure for one-pot synthesis of conjugated
diene carbonyl compounds in CH2Cl2
The general procedure is illustrated by the preparation of 10e. To
a solution of 8 (85 mg, 0.316 mmol) and ethyl vinyl ketone (94 mL,
0.947 mmol) in CH2Cl2 (1.6 mL) was added 3 (4.0 mg, 0.0064 mmol,
2.0 mol %), and the mixture was refluxed for 15 h. Then the reaction
mixture was cooled to 22 ꢀC, and DBU (94
mL, 0.63 mmol) was
added dropwise and stirred for another 1 h at the same tempera-
ture. HCl (1.0 M, 3 mL) was added and the mixture was extracted
with CH2Cl2. The combined organic layer was washed with water,
dried, and the solvent was removed under reduced pressure to give
a brown residue, which was chromatographed (hexane–ethyl ac-
etate, 13:1) to give 10e (56 mg, 96%) as a white solid.
10. Wahler, D.; Badalassi, F.; Crotti, P.; Reymond, J.-L. Chem.dEur. J. 2002, 8, 3211–
3228.
11. (a) Garber, S. B.; Kingsbury, J. S.; Grey, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 8168–8179; (b) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen,
J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol.
Chem. 2004, 2, 8–23.
12. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783–3784.
4.8. Procedure for one-pot synthesis in PTS/H2O (7a)
13. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
14. Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751–1753.
15. (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-Sol-
uble 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.
Olefin
1 (39 mg, 0.20 mmol), tert-butyl acrylate (59 mL,
0.40 mmol), and catalyst 3 (2.53 mg, 0.004 mmol) were sequen-
tially 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 (2.5% by weight, 1.0 mL) was added
via syringe and the resulting emulsion was allowed to stir at 40 ꢀC
16. Lipshutz, B. H.; Aguinaldo, G. T.; Ghorai, S.; Voigtritter, K. Org. Lett. 2008, 10,
1325–1328.
17. Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Org. Lett. 2006, 8, 5069–5072.
for 15 h. Then DBU (60
reaction mixture and stirred for another 1 h at 22 ꢀC. The
mL, 0.60 mmol) was added dropwise to the