Enyne Metathesis: A Catalytic, Cross-Selective Diene Synthesis

Article abstract of DOI:10.1055/s-2003-44375

Methods for the synthesis of 1,3-dienes by intermolecular enyne metathesis are described. A brief overview of enyne metathesis is provided with a discussion of the scope and limitations with respect to reactants and catalyst. The surge of recent interest in metathesis generally and the cross enyne metathesis specifically, has closely matched the development of the functional group-tolerant Grubbs' carbene catalysts.

Full text of DOI:10.1055/s-2003-44375

466
PRACTICAL SYNTHETIC PROCEDURES
Enyne Metathesis: A Catalytic, Cross-Selective Diene Synthesis
E
nyne Metath
t
esis even T. Diver,* Anthony J. Giessert
Department of Chemistry, University at Buffalo, The State University of New York, Amherst,
NY 14260, USA
E-mail: diver@buffalo.edu
PSP
Received 16 October 2003
No16
Abstract: Methods for the synthesis of 1,3-dienes by intermolecular enyne metathesis are described. A brief overview of enyne metathesis
is provided with a discussion of the scope and limitations with respect to reactants and catalyst. The surge of recent interest in metathesis
generally and the cross enyne metathesis specifically, has closely matched the development of the functional group-tolerant Grubbs’ car-
bene catalysts.
Key words: enyne metathesis, Grubbs’ carbene catalysts, 1,3-dienes
procedure 1
OAc
OAc
Ru gen-2 (5 mol %)
Ph
Ph
(1)
ethene (60 psig)
CH2Cl2, rt, 24 h
1
2 (95 %)
procedure 2
OBz
OBz
Ru gen-2 (5 mol %)
(2)
5 (3)
(4)
1-hexene (9 equiv.)
benzene, reflux, 24 h
4 (97 %)
6 (97 %)
8 (91 %)
3
5
procedure 3
Ru gen-2 (5 mol %)
OC2H
TBDPSO
TBDPSO
(9 equiv.)
OEt
benzene, reflux, 10 min
procedure 4
BzS
Ru gen-2 (5 mol %)
BzS
OC2H5
(9 equiv.)
OEt
ethene (5 psig)
7
benzene, rt, 20 h
procedure 5
Ru gen-2 (5 mol %)
OBz
OBz
(5)
(6)
OTBS
(9 equiv.)
ethene (5 psig)
benzene, rt, 20 h
OTBS
9 (91 %)
3
procedure 6
Ru gen-2 (5 mol %)
BzO
BzO
cyclopentene (4 equiv.)
CH2Cl2, reflux, 16 h
(high dilution)
10
11 (76 %)
Mes
N
N Mes
Cl
Mes
N
N Mes
Cl
Mes
N
N Mes
Cl
Ru
O
Ru
py Ru
Ph
Ph
Cl
i-Pr
Cl
Cl
PCy3
py
12
13
14
py = 3-bromopyridine
Ru gen-2
Scheme 1 Examples of intermolecular (cross) enyne metathesis
SYNTHESIS 2003, No. 3, pp 0466–0471
x
x
.
x
x
.2
0
0
3
Advanced online publication: 09.12.2003
DOI: 10.1055/s-2003-44375; Art ID: Z15403SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Enyne Metathesis
467
Enyne metathesis has emerged as a synthetically useful in catalyst design and improvements in catalyst initiation
diene synthesis. Enyne metathesis joins alkene and alkyne profile continue.7
starting materials through carbon-carbon bond coupling
and pi-reorganization to yield 1,3-dienes.1 The diene
products are useful building blocks for the assembly of Scope of the Reaction
ring systems and more complex molecules, typically
through cycloaddition. The Grubbs’ family of ruthenium The reactants in the enyne metathesis are alkenes and
carbenes have revolutionized alkene metathesis because alkynes, reacting through a ruthenium carbene catalyst.
of their functional group tolerance.2 The more active N- For each component, the scope and limitations will be dis-
heterocyclic carbene bearing initiators, exemplified by the cussed.
second generation Grubbs’ benzylidene complex (Ru
gen-2), retain the high functional group tolerance charac-
teristic of the ruthenium carbenes and yet provide in-
Alkene
creased reactivity necessary for catalysis in demanding The intermolecular reaction is an atom economical syn-
systems.3 As a result, ruthenium carbenes have been wide- thesis of dienes. However, the alkene component is al-
ly embraced by the synthetic community.
ways used in molar excess (unlike the ring-closing enyne
metathesis which is necessarily equimolar in alkene and
alkyne). Typically three mole equivalents of alkene are
used. A range of 1-alkenes react with alkynes, including
electron-rich enol ethers (procedures 3–5). Until recently,
the intermolecular reaction was considered limited to 1-
alkenes. This preconception may have been built upon the
accepted mechanism invoking ruthenium methylidenes.
A better estimate is based on whether the alkene under-
goes initiation by the precatalyst.8 Internal alkenes such as
cycloalkenes give the cross metathesis which has been
used as a ring synthesis (procedure 6). The intermolecular
enyne metathesis is quite tolerant of allylic oxygen func-
tionality: acetates, alkyl and silyl ethers. However, free al-
cohols in the allylic position are not well behaved. 1-
Substituted allyl alcohol derivatives have not been used in
cross enyne metathesis and other allylic heteroatoms such
as nitrogen and sulfur have not been reported.9 Allylic and
homoallylic functionality must be considered since coor-
dination is possible, but more remote functionality on the
alkene does not interfere with cross enyne metathesis. The
diene products are kinetically-stable using the first gener-
ation Grubbs’ catalyst.10 Using the more reactive Ru gen-
2 carbene, cross metathesis can be initiated from a diene
onto another alkene.4,5e,11
Enyne metathesis can be separated into two categories dif-
ferentiated by the molecularity of the reaction. With a 1,n-
enyne, a ring-closing enyne metathesis takes place to pro-
vide a 1-vinyl-cycloalkene. This intramolecular version of
the reaction works well in a variety of functional group-
rich environments and produces a single regioisomer and
a single stereoisomer in the newly formed diene. Often the
intramolecular nature of the reaction makes productive
metathesis fast relative to catalyst trapping and decompo-
sition pathways. The intermolecular, or cross metathesis,
is potentially more powerful as it represents a fragment
coupling approach to diene synthesis. The intermolecular
reaction is atom economical and is inherently cross selec-
tive. A weakness of the intermolecular reaction is gener-
ally the inability to control product stereochemistry.4 In
this report, several synthetic procedures for intermolecu-
lar enyne metathesis are detailed (Scheme 1).
The enyne metathesis has its roots in ring-opening met-
athesis polymerization (ROMP) due to the work of Katz.1a
Since that time, landmark studies by Grubbs1b and Mori1c
independently established the role of ruthenium carbenes
in ring-closing enyne metathesis applications, and these
have been widely used in synthesis ranging from prepara-
tion of carbo- and heterocycles to natural product synthe-
sis.1f–h The intermolecular application of enyne metathesis
came in 1997 with two groups reporting the cross reaction
using the first generation Grubbs’ carbene. Blechert’s
group disclosed the cross enyne metathesis of allyltrime-
thylsilane with terminal alkynes;1d and Mori and cowork-
ers reported a cross ethylene-alkyne metathesis.1e Since
that time, metathesis applications in the intermolecular
manifold have continued to develop including those con-
ducted on polymeric support,5a–d to set up tandem
reactions5e and to explore functional group scope of the
reaction.5f,g The reaction mechanism currently accepted
for enyne cross metathesis is based on that proposed by
Blechert.1d In the past couple of years, most investigators
shifted to catalysis using the second generation initiator,
12 (Ru gen-2).3,6 There is also an increased use of the
Hoveyda carbene 13 which is phosphine-free.7a–g The Ru
gen-2 carbene is commercially-available or can be pre-
pared as described by the Grubbs group.3b,g Developments
Alkyne
Terminal alkynes are used in cross enyne metathesis, al-
though in a few cases internal alkynes have been reacted.
In the original examples of ethylene-alkyne cross met-
athesis, remote functionality in the alkyne sometimes af-
fected the success of the reaction. Recent developments
based on the second generation Grubbs’ carbene 12 have
overcome these limitations. The propargylic position can
be -substituted, and chiral centers remain intact during
enyne metathesis.5g,h With the Ru gen-2 complex, propar-
gylic ethers, free alcohols and thiol esters were found to
undergo metathesis with ethylene.5f,g Nonetheless, coordi-
nation by more proximal functional groups may siphon
active catalyst out of the catalytic cycle, retarding cataly-
sis and possibly leading to catalyst decomposition. Practi-
cally speaking, this may not stop the reaction but may
slow the reaction rate down, requiring higher tempera-
Synthesis 2003, No. 3, 466–471 © Thieme Stuttgart · New York

468
S. T. Diver, A. J. Giessert
PRACTICAL SYNTHETIC PROCEDURES
tures, additional catalyst to be added or the use of higher
initial catalyst loading.
Ethylene
Ethylene has served both as an alkene reactant in cross
enyne metathesis, and has been used as an additive. In the
most familiar application, ethylene is employed as an ad-
ditive to promote ring-closing enyne metathesis by main-
taining catalyst lifetime, ‘Mori’s conditions.’1e Mori’s
conditions utilize an ethylene balloon to maintain ethyl-
ene atmosphere. As an alkene reactant, ethylene can be
employed at balloon14a or elevated pressure (procedure
1).5f However in the cross enyne metathesis of 1-alkene
and alkyne, ethylene is usually unwanted since it may
compete with the alkene-alkyne cross metathesis. Ethyl-
ene is produced as a byproduct from 1-alkene reactant un-
dergoing competitive alkene-alkene metathesis.15 As a
result, ethylene can compete with 1-alkene-alkyne cross
metathesis providing a 1,3-butadiene byproduct. This side
reaction is often seen in less reactive alkynes and can be
retarded by using an excess of alkene or by constant argon
sparge/reflux to remove generated ethylene. In special-
ized cases, the cross enyne metathesis with ethylene addi-
tive has resulted in increased reactivity (with enol
ethers)14b and has influenced stereoselectivity (large ex-
cess of 1-alkene).4 A specialized case where ethylene
served as a helping alkene is shown in procedures 4 and 5
overcoming poor reactivity and averting thermal decom-
position by facilitating catalysis at lower reaction temper-
atures.
Catalyst
The cross enyne metathesis is catalyzed by ruthenium car-
benes.2,3,7 The metal salt-catalyzed reaction (e.g. with
PtCl2) is unknown for the intermolecular enyne metathe-
sis although well-documented in the ring-closing met-
athesis (enyne bond reorganization).12 Also, the related
Dixneuf catalyst system,7l as in situ preparation of (p-
cymene)Ru(H2IMes)Cl2, performs ring-closing enyne
metathesis, but the cross reaction has not been reported
using this catalyst. With the second generation ruthenium
carbenes featuring the N-heterocyclic carbene ligand, ini-
tiation is not considered a kinetic problem for enyne met-
athesis. In other words, the cross enyne metathesis is not
likely to benefit from faster initiation rate alone. Nonethe-
less, the Hoveyda–Blechert7a–d class of initiator and the
Grubbs’ pyridine solvate 147g,h have been used in enyne
metathesis. In one case, the Hoveyda catalyst 13 produced
superior results compared to Ru gen-2.5e
From a practical perspective, increased catalyst loading
can often be used in difficult, turnover-challenged cases.
Catalyst loading is typically on the order of 5–20 mole
percent and it is unusual to see catalyst loadings below 5
mole percent. From an operational standpoint, when cross
metathesis stalls out, addition of more catalyst usually
leads to complete consumption of the alkyne reactant. We
have observed degraded activity of our synthesized batch-
es of Ru gen-2 after extended storage. The simplest diag-
nostic tools are proton and 31P NMR in benzene. Multiple
phosphorous resonances correlate with diminished activi-
ty. Older samples of catalyst can be purified on silica gel
by flash chromatography.7a,b
Other Reaction Variables
The cross enyne metathesis is conducted in CH2Cl2 or
benzene at temperatures between room temperature and
reflux.
The following procedures represent the intermolecular
(cross) enyne metathesis. In the following examples, the
second generation Grubbs’ carbene 12 is employed. Eth-
ylene is used as the alkene reactant at elevated pressure in
procedure 1; 1-hexene is used in procedure 2 and electron-
rich alkenes are reacted in procedures 3–5. For substituted
1-alkenes, the procedure 2 provides a good starting point,
and reactivity is observed with the commercially available
Grubbs’ carbene 12 even at room temperature. Cyclopen-
tene serves as the alkene reactant in procedure 6 and this
requires high dilution reaction conditions using a syringe
pump. Ethylene is also employed as a helping alkene in
procedures 4 and 5, maintained at 5 psig in a pressure bot-
tle. These specialized conditions are used to overcome the
poor reactivity associated with ruthenium Fischer carbene
complexes. The examples utilize a variety of terminal
alkynes with various heteroatom substituents at the prop-
argylic position. (Alkynes that do not contain propargylic
heteroatoms undergo cross metathesis as do internal
alkynes,16 although these examples are not shown.) Repe-
tition of procedures 2 and 4 using undistilled reagents and
solvent gave comparable yields.
High catalyst loadings require improved purification pro-
cedures to remove ruthenium byproducts. This may be es-
pecially critical in library synthesis and for the preparation
of pharmaceuticals. There are three procedures available
to remove spent ruthenium catalyst and decomposition
products from the crude reaction mixture.13 Grubbs and
Maynard showed that a water-soluble phosphine could be
used for extractive removal of ruthenium byproducts.13a
This is a very simple method. Mostly, this has not been
used in synthesis labs because the trialkylphosphine
(HOCH2)3P must be prepared (e.g. from the commercial-
ly-available precursor, (HOCH2)4PCl) and stored in a
glovebox or under rigorous exclusion of air. Paquette re-
ported an oxidation of ruthenium byproducts in a crude re-
action mixture using lead tetraacetate (LTA), followed by
column chromatography.13b Georg et al. reported a similar
procedure using DMSO or Ph3PO as oxidant, which are
preferable to LTA.13c The Georg procedure is very conve-
nient, but since the oxidation is relatively slow, it requires
overnight reaction times. The ease and mildness of the
procedure has attracted synthetic chemists who may have
only a transient or tactical interest in the enyne metathesis.
Synthesis 2003, No. 3, 466–471 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Enyne Metathesis
469
Reactions were conducted under an Ar atmosphere unless otherwise
noted. Benzene was distilled from CaH2 or drawn from a solvent pu-
rifier (alumina and Q5) immediately before use. CH2Cl2 was dis-
tilled from CaH2 or drawn from a solvent purifier (alumina)
immediately before use. Ethyl vinyl ether and cyclopentene were
distilled from Na. 1-Hexene was purchased from Aldrich and used
without purification. Ruthenium carbenes 12 (Ru gen-2)3a,g or 137b
were either synthesized or obtained from Materia. Carbene 12 (Ru
gen-2) is also commercially available from Sigma-Aldrich Chemi-
cal Co. Pyridine solvate 14 was synthesized as reported.7h Alkynes
purchased from Aldrich Chemical Company were distilled before
use. Polymer grade ethylene was purchased from Matheson and
used without purification. Column chromatography was carried out
on Merck silica gel 60 (230–400 mesh). GC was performed on a
DB-wax capillary column (J & W Scientific, 0.25 mm × 30 m, 0.25
m film thickness) with a thermal gradient (40 °C for 4 min then 25
°C/min until 280 °C was reached and maintained at 280 °C for 16.4
min). 1H NMR spectra were recorded at 400 MHz, or 500 MHz and
13C NMR spectra at either 75 MHz or 125 MHz in the indicated sol-
vent. 1H NMR spectra were referenced on the TMS signal for
CDCl3 solvent. The 13C NMR spectra were referenced at 77.0 ppm
for CDCl3.
Hz, 2 H), 1.52 (d, J = 7.0 Hz, 3 H), 1.40–1.26 (m, 4 H), 0.87 (t, J =
7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): = 165.6, 146.4, 132.8, 131.7, 130.5,
129.5, 128.7, 128.3, 112.1, 70.5, 32.8, 31.3, 22.1, 20.4, 13.9.
HRESI: m/z [M + Na] calcd for C17H22O2: 281.1518; found:
281.1503.
This procedure was repeated in the atmosphere using unpurified,
commercially available 1-hexene and reagent grade benzene to give
the diene 4 in 92% yield.
Procedure 3
E/Z Ethyl (4-tert-Butyl-diphenyl-siloxy-3-methylene-1-butenyl)
Ether (6)16
Into an oven-dried Schlenk tube (50 mL capacity) equipped with
magnetic stirbar and cold-finger condenser were added Ru gen-2
(42.5 mg, 0.05 mmol, 5 mol%), 1-diphenyl-(t-butyl)-siloxy-2-pro-
pyne (294 mg, 1.0 mmol, 1.0 equiv) in 10 mL benzene, and ethyl
vinyl ether (648 mg, 862 L, 9.0 mmol, 9.0 equiv). The reaction
vessel was then heated to reflux in an oil bath with stirring for 10
min, cooled to r.t., filtered through a plug of silica gel (elution with
CH2Cl2) and concentrated in vacuo (rotatory evaporator) to yield a
dark colored oil. The oil was then purified by flash chromatography
(elution with 5% EtOAc–hexane) yielding 355 mg of 6 (97%) as a
clear oil; analytical TLC: Rf 0.38 (5% EtOAc–hexane). 1H NMR in-
dicated a 0.47:1.0 ratio of Z:E isomers.
Procedure 1
1-Phenyl-2-acetoxy-3-methylene-4-pentene (2)5f
To an oven dried 90 mL Fischer–Porter bottle were added Ru gen-
2 (42.5 mg, 0.05 mmol, 5 mol%), and 1-phenyl-2-acetoxy-3-butyne
(1) (188 mg, 1.0 mmol, 1 equiv) in freshly distilled CH2Cl2 (4 mL).
The pressure vessel was sealed and purged with ethylene (4 × 60
psig) then charged with ethylene (80 psig) and stirred for 24 h at r.t.
The resulting dark colored solution was filtered through a plug of
silica (elution with CH2Cl2), concentrated in vacuo (rotatory evap-
orator), and purified by flash chromatography (elution with 10%
EtOAc–hexane) to yield 205 mg of 2 (95%) as a clear oil; analytical
TLC: Rf 0.48 (25% Et2O–hexanes).
FT-IR (thin film): 2934, 2896, 2858, 1667, 1471, 112, 909, 737
cm–1.
1H NMR (500 MHz, CDCl3): = 7.71–7.64 (m, 5.88 H), 7.44–7.30
(m, 8.82 H), 6.54 (d, J = 13.0 Hz, 1 H), 5.93 (d, J = 7.0 Hz, 0.47 H),
5.54 (d, J = 13.0 Hz, 1 H), 5.42 (s, 0.47 H), 5.29 (s, 0.47 H), 5.09 (s,
1 H), 4.90 (s, 1 H), 4.81 (d, J = 7.0 Hz, 0.47 H), 4.39 (s, 0.94 H),
4.27 (s, 2 H), 3.78–3.71 (m, 2.94 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.13
(t, J = 7.0 Hz, 1.41 H), 1.08 (s, 4.23 H), 1.06 (s, 9 H).
13C NMR (125 MHz, CDCl3): = 147.3, 146.1, 142.9, 142.5, 135.6,
135.5, 133.5, 132.9, 129.8, 129.6, 127.7, 127.6, 110.1, 109.6, 105.9,
104.1, 68.6, 66.2, 65.3, 64.3, 26.9, 26.8, 19.4, 19.3, 15.1, 14.8.
FT-IR (film): 3036, 2919, 1742, 1375, 1241, 1023, 911 cm–1.
1H NMR (400 MHz, CDCl3): = 7.28–7.16 (m, 5 H), 6.34 (dd, J =
18.0, 11.0 Hz, 1 H), 5.47 (dd, JBX = 8.5 Hz, JAX = 4.7 Hz, 1 H), 5.42
(d, J = 18.0 Hz, 1 H), 5.15 (d, J = 11.0 Hz, 1 H), 5.14 (s, 1 H), 5.10
(s, 1 H), 3.05 (AB q, JAB = 14.0 Hz, JAX = 4.7 Hz, 1 H), 2.76 (AB q,
HREI: m/z [M + Na] calcd for C23H30O2Si: 389.1915; found:
389.1923.
J
AB = 14.0 Hz, JBX = 8.5 Hz, 1 H), 2.00 (s, 3 H).
Procedure 4
13C NMR (125 MHz, CDCl3): = 169.9, 144.7, 137.4, 135.6, 129.3,
128.2, 126.5, 115.9, 114.8, 73.8, 40.4, 21.0.
Thiobenzoic Acid S-(5-ethoxy-3-methylene-pent-4-enyl) Ester
(8)14b
HRFAB–MS: m/z [M + Na] calcd for C14H16O2: 239.1050, found:
239.1052.
To a 90 mL Fischer-Porter bottle were added Ru gen-2 (10 mg,
0.0118 mmol, 0.5 equiv), homopropargyl thiobenzoate 7 (45.0 mg,
0.236 mmol, 1 equiv) in benzene (4 mL), and ethyl vinyl ether (203
L, 153 mg, 2.12 mmol, 9 equiv), the pressure vessel was purged
with ethylene (4 × 5 psig) and sealed (5 psig ethylene). The reaction
was allowed to stir at r.t. for 20 h, depressurized, filtered through sil-
ica (1 inch plug elution with CH2Cl2) and concentrated in vacuo
(rotatory evaporator) to yield a yellow-orange oil. The product was
further purified by flash column chromatography (elution with hex-
ane containing 1% triethylamine) to yield 56.4 mg of 8 (91%) as a
clear oil; GC retention times of 16.47 and 16.65 min (integral not
determined because of overlapping peaks); analytical TLC Rf 0.28
(10% EtOAc–hexane). H NMR indicated a 0.36:1.0 ratio of Z:E
isomers.
FT-IR (thin film): 3054, 2986, 1719, 1665, 1448, 1421, 1208 cm–1.
1H NMR (500 MHz, CDCl3) = 7.96–7.91 (m, 2.72 H), 7.56–7.51
(m, 1.36 H), 7.44–7.39 (m, 2.72 H), 6.79 (d, J = 13.0 Hz, 1 H), 5.97
(d, J = 7.0 H, 0.36 H), 5.56 (d, J = 13.0 Hz, 1 H), 5.12 (s, 0.36 H),
4.86 (s, 0.36 H), 4.84 (s, 1 H), 4.81 (d, J = 7.0 Hz, 0.36 H), 4.75 (s,
1 H), 3.88–3.80 (m, 2.72 H), 3.22–3.16 (m, 2.72 H), 2.62 (t, J = 6.5
H, 0.72 H), 2.48 (t, J = 6.5 H, 2 H), 1.29 (t J = 6.5 Hz, 4.08 H).
Procedure 2
(4E)-2-Benzyloxy-3-methylene-4-nonene (4)
Into an oven-dried Schlenk tube (50 mL capacity) equipped with
magnetic stirbar and cold-finger condenser were added of Ru gen-
2 (42.5 mg, 0.05 mmol, 5 mol%), 1-methyl propargyl benzoate (174
mg, 1.0 mmol, 1.0 equiv) and freshly distilled benzene (10 mL), fol-
lowed by 1-hexene (757 mg, 1.13 mL, 9.0 mmol, 9.0 equiv). The re-
action vessel was then heated to reflux in an oil bath with stirring
for 24 h, cooled to r.t., filtered through a plug of silica gel (elution
with CH2Cl2) and concentrated in vacuo (rotatory evaporator) to
yield a dark colored oil. The oil was then purified by flash chroma-
tography (elution with 5% EtOAc–hexane) yielding 252 mg of 4
(97%) as a clear oil; GC retention time of 15.03 min; analytical
TLC: Rf 0.44 (10% EtOAc–hexane).
1
FT-IR (thin film): 2959, 2928, 2874, 1712, 1598, 1447 cm–1.
1H NMR (500 MHz, CDCl3): = 8.06 (d, J = 7.0 Hz, 2 H), 7.53 (t,
J = 6.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 6.05 (d, J = 16.5 Hz, 1
H), 5.89–5.77 (m, 2 H), 5.18 (s, 1 H), 5.05 (s, 1 H), 2.10 (q, J = 7.0
Synthesis 2003, No. 3, 466–471 © Thieme Stuttgart · New York

470
S. T. Diver, A. J. Giessert
PRACTICAL SYNTHETIC PROCEDURES
13C NMR (125 MHz, CDCl3): = 192.2, 191.9, 148.2, 146.0, 142.1,
141.9, 137.3, 137.1, 133.3, 133.1, 128.6, 128.5, 127.2, 127.1, 114.1,
111.4, 107.6, 105.7, 68.9, 65.6, 36.5, 33.4, 28.6, 28.1, 15.3, 14.8.
1H NMR (500 MHz, CDCl3): = 8.05 (m, 2 H), 7.54 (t, J = 7.0 Hz,
1 H), 7.42 (t, J = 8.0 Hz, 2 H), 6.01 (t, J = 5.0 Hz, 1 H), 5.92 (m, 1
H), 5.83 (dd, J = 12.0, 2.0 Hz, 1 H), 4.75 (s, 2 H), 2.35 (d, J = 4.5
Hz, 4 H), 1.87 (m, 2 H).
13C NMR (125 MHz, CDCl3): = 166.5, 134.8, 133.5, 132.8, 131.6,
130.3, 129.6, 128.2, 125.6, 70.7, 31.7, 30.4, 25.9.
HRESI: m/z [M + Na] calcd for C15H18O2S: 285.0925; found:
285.0931.
This procedure was repeated in the atmosphere using unpurified
ethyl vinyl ether and reagent grade benzene to give the ethyl dienol
ether 8 in 87% yield.
HRMS (EI+): m/z calcd for C15H16O2: 228.1145; found: 228.1147.
References
Procedure 5
Benzoic Acid 4-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-2-
(1) (a) Katz, T. J.; Sivavec, T. M. J. Am. Chem. Soc. 1985, 107,
737. (b) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am.
Chem. Soc. 1994, 116, 10801. (c) Kinoshita, A.; Mori, M.
Synlett 1994, 1020. (d) Stragies, R.; Schuster, M.; Blechert,
S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2518.
methylene-but-3-enyl Ester (9)16
To a 90 mL Fischer-Porter bottle were added Ru gen-2 (10 mg,
0.0118 mmol, 0.05 equiv), 1-methyl propargyl benzoate (41.1 mg,
0.236 mmol, 1 equiv) in benzene (4 mL), and TBSOCH=CH2 (336
mg, 2.12 mmol, 9 equiv), the pressure vessel was purged with eth-
ylene (4 × 5 psig) and sealed (5 psig ethylene). The reaction was al-
lowed to stir at r.t. for 20 h, depressurized, filtered through silica (1
inch plug elution with CH2Cl2) and concentrated in vacuo to yield a
yellow-orange oil. The product was further purified by flash column
chromatography (elution with hexane containing 1% Et3N) to yield
72.2 mg of 9 (91%) as a clear oil; GC retention times of 16.22 and
16.31 min (integral not determined because of overlapping peaks);
analytical TLC (10% EtOAc–hexane): Rf 0.26. 1H NMR indicated
a 1.59:1.0 ratio of Z:E isomers.
(e) Kinoshita, A.; Sakakibara, N.; Mori, M. J. Am. Chem.
Soc. 1997, 119, 12388. (f) Kinoshita, A.; Mori, M. J. Org.
Chem. 1996, 61, 8356. (g) Reviews: Mori, M. Top.
Organomet. Chem. 1998, 1, 133. (h) See also: Poulsen, C.
S.; Madsen, R. Synthesis 2003, 1.
(2) (a) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J.
W. J. Am. Chem. Soc. 1992, 114, 3974. (b) Fu, G. C.;
Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115,
9856. (c) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1997, 119, 3887. (d) Schwab, P.; Grubbs, R. H.;
Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100.
FT-IR (thin film): 3065, 3032, 2960, 1496, 1454, 1073 cm–1.
(e) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.;
Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 58. (f) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18.
1H NMR (500 MHz, CDCl3): = 8.06–8.02 (m, 5.18 H), 7.52–7.36
(m, 7.77 H), 6.73 (d, J = 13.0 Hz, 1 H), 6.28 (d, J = 7.0 Hz, 1.59 H),
5.83 (q, J = 7.0 Hz, 1.59 H), 5.71–5.63 (m, 2 H), 5.41 (s, 1.59 H),
5.23 (s, 1.59 H), 5.01 (s, 1 H), 4.93–4.90 (m, 2.59 H), 1.52–1.45 (m,
7.77 H), 0.93 (s, 9 H), 0.87 (s, 14.31 H), 0.16 (s, 9.54 H), 0.11 (s, 6
H).
13C NMR (125 MHz, CDCl3): = 165.9, 165.8, 144.3, 143.8, 142.9,
141.3, 133.1, 132.9, 131.1, 129.9, 129.8, 128.6, 128.5, 128.4, 111.9,
111.8, 110.2, 106.3, 73.5, 71.7, 25.8, 25.5, 21.0, 20.5, 18.5, 18.3,
–5.04, –5.16.
(3) (a) Weskamp, T.; Schattenmann, W. C.; Spiegler, M.;
Herrmann, W. A. Angew. Chem. Int. Ed. 1998, 37, 2490.
(b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (c) Huang, J.; Stevens, E. D.; Nolan, S. P.;
Petersen, J. L. J. Am. Chem. Soc. 1999, 121, 2674.
(d) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247. (e) Ackermann, L.;
Fürstner, A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A.
Tetrahedron Lett. 1999, 40, 4787. (f) Fürstner, A.;
Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.;
Mynott, R.; Stelzer, F.; Thiel, O. R. Chem.–Eur. J. 2001, 7,
3236. (g) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.;
Wilhelm, T. E.; Scholl, M.; Choi, T.-L.; Ding, S.; Day, M.
W.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 2546.
(4) In certain cases, the reaction does produce the more stable E-
isomer, and when E,Z-mixtures are formed, it is likely that
the reaction is kinetically-controlled. Equilibrium control:
Lee, H.-Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5,
1855.
(5) For solid supported reactions see the following:
(a) Schuerer, S. C.; Blechert, S. Synlett 1999, 1879.
(b) Schuerer, S. C.; Blechert, S. Chem. Commun. 1999,
1203. (c) Schuster, M.; Blechert, S. Tetrahedron Lett. 1998,
39, 2295. (d) Schuerer, S. C.; Blechert, S. Synlett 1998, 166.
(e) Tandem, cross metathesis: Royer, F.; Vilain, C.;
Elkaiem, L.; Grimaud, L. Org. Lett. 2003, 5, 2007.
(f) Functional group scope: Smulik, J. A.; Diver, S. T. Org.
Lett. 2000, 2, 2271. (g) See also: Smulik, J. A.; Giessert, A.
J.; Diver, S. T. Tetrahedron Lett. 2002, 43, 209. (h)Smulik,
J. A.; Diver, S. T. J. Org. Chem. 2000, 65, 1788.
HRESI: m/z [M + Na] calcd for C19H28O3Si: 355.1708; found
355.1690.
Procedure 6
Benzoic Acid 1-Cyclohepta-1,6-dienyl-methyl Ester (11)8b
Into an oven-dried Schlenk tube (100 mL capacity) equipped with
magnetic stirbar and a cold finger condenser, was added CH2Cl2 (50
mL) followed by Ru gen-2 (106 mg, 0.125 mmol, 5 mol%) and the
solution was heated to reflux. Propargyl benzoate (400 mg, 2.5
mmol, 1 equiv) and cyclopentene (170 mg, 220 L, 10.0 mmol)
were dissolved in 5.0 mL of CH2Cl2 and this solution was then add-
ed to the catalyst solution in CH2Cl2 at 45 °C over a period of 16 h
by means of a gas-tight syringe (syringe pump). After the addition
was complete, the reaction mixture was stirred in the oil bath for an
additional 45 min. The reaction mixture was concentrated in vacuo
(rotatory evaporator), then partially purified by passing through a
small plug of silica gel (1 inch, elution with CH2Cl2) to remove the
catalyst and the solvent was removed in vacuo. The crude oil thus
obtained was further purified by silica gel flash chromatography
(elution with 4% EtOAc–hexane) to provide diene 11 as a pale yel-
low oil. The product was then redissolved in ca. 5 mL CH2Cl2 and
DMSO (177 L, 2.5 mmol) was added. This solution was stirred at
r.t. for a period of 18 h after which the solvent was removed in vac-
uo and the yellow oil was further purified by flash column chroma-
tography using silica gel (elution with 4% EtOAc–hexane) yielding
11 as a colorless oil (571 mg, 76% yield); analytical TLC: Rf 0.35
(7% EtOAc–hexane).
(6) Two anomalies, see: (a) Poulsen, C. S.; Madsen, R. J. Org.
Chem. 2002, 67, 4441. (b) Clark, S. J.; Elustondo, F.;
Trevitt, G. P.; Boyall, D.; Robertson, J.; Blake, A. J.; Wilson,
C.; Stammen, B. Tetrahedron 2002, 58, 1973. (c) Higher
temperatures can lead to epimerization in certain cases: Guo,
FT-IR (thin film): 2926, 1717, 1451, 1313, 1111, 711 cm–1.
Synthesis 2003, No. 3, 466–471 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Enyne Metathesis
471
H.; Madhushaw, R. J.; Shen, F.-M.; Liu, R.-S. Tetrahedron
2002, 58, 5627.
(8) (a) The second generation initiators transalkylidenate with
internal and geminal alkenes, see e.g.: Chatterjee, A. K.;
Grubbs, R. H. Org. Lett. 1999, 1, 1751. (b) There is one
reported case of an internal alkene giving cross enyne
metathesis: Kulkarni, A. A.; Diver, S. T. Org. Lett. 2003, 5,
3463.
(9) (a) Homoallylic amides have been attempted, but their
failure led to use of homopropargyl tosylates which were
converted into homoallylic amides after enyne metathesis,
see: Rodriguez-Conesa, S.; Candal, P.; Jimenez, C.;
Rodriguez, J. Tetrahedron Lett. 2001, 42, 6699. (b) See ref.
5d.
(10) (a) Stragies, R.; Voigtmann, U.; Blechert, S. Tetrahedron
Lett. 2000, 41, 5465. (b) Randl, S.; Lucas, N.; Connon, S. J.;
Blechert, S. Adv. Synth. Catal. 2002, 344, 631.
(11) Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469.
(12) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102,
813.
(13) Purification procedures: (a) Maynard, H. D.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 4137. (b) Paquette, L. A.;
Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.; Mendez-
Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259. (c) Ahn, Y.
M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411.
(14) Ethylene protective effect: (a) Mori, M.; Sakakibara, N.;
Kinoshita, A. J. Org. Chem. 1998, 63, 6082. (b) Reactivity
enhancement: Giessert, A. J.; Brazis, N.; Diver, S. T. Org.
Lett. 2003, 5, 3819. (c) Stereoselection: ref. 4.
(7) Catalyst Development. Hoveyda-Blechert class:
(a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J. Jr.;
Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791.
(b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 8168. (c) Gessler, S.;
Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41, 9973.
(d) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S.
Synlett 2001, 430. (e) Wakamatsu, H.; Blechert, S. Angew.
Chem. Int. Ed. 2002, 41, 794. (f) Wakamatsu, H.; Blechert,
S. Angew. Chem. Int. Ed. 2002, 41, 2403. (g) Grela, K.;
Harutyunyan, S.; Michrowska, A. Angew. Chem. Int. Ed.
2002, 41, 4038. (h) Pyridine solvates: Sanford, M. S.; Love,
J. A.; Grubbs, R. H. Organometallics 2001, 20, 5314.
(i) See also: Love, J. A.; Morgan, J. P.; Trnka, T. M.;
Grubbs, R. H. Angew. Chem. Int. Ed. 2002, 41, 4035.
(j) For in situ catalysts, see the following: Jafarpour, L.;
Huang, J.; Stevens, E. D.; Nolan, S. P. Organometallics
1999, 18, 3760. (k) Louie, J.; Grubbs, R. H. Angew. Chem.
Int. Ed. 2001, 40, 247. (l) Ackermann, L.; Bruneau, C.;
Dixneuf, P. H. Synlett 2001, 397. (m) For solid supported
ruthenium catalysts, see the following reference: Ahmed,
M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.;
Procopiou, P. A. Tetrahedron Lett. 1999, 40, 8657.
(n) Ahmed, M.; Arnauld, T.; Barrett, A. G. M.; Braddock, D.
C.; Procopiou, P. A. Synlett 2000, 1007. (o) Schurer, S. C.;
Gessler, S.; Buschmann, N.; Blechert, S. Angew. Chem. Int.
Ed. 2000, 39, 3898. (p) Yao, Q. Angew. Chem. Int. Ed.
2000, 39, 3896. (q) Kingsbury, J. S.; Garber, S. B.; Giftos, J.
M.; Gray, B. L.; Okamoto, M. M.; Farrer, R. A.; Fourkas, J.
T.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2001, 40, 4251.
(r) Chiral ruthenium catalysts: Seiders, T. J.; Ward, D. W.;
Grubbs, R. H. Org. Lett. 2001, 3, 3225. (s)VanVeldhuizen,
J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 4954.
(15) We have seen this in cross metathesis between 1-hexene and
3-benzoyloxy-butyne. It has been reported for internal
alkynes, see: Stragies, R.; Voigtmann, U.; Blechert, S.
Tetrahedron Lett. 2000, 41, 5465.
(16) Giessert, A. J.; Snyder, L.; Markham, J.; Diver, S. T. Org.
Lett. 2003, 5, 1793.
Synthesis 2003, No. 3, 466–471 © Thieme Stuttgart · New York