Ethylene-Promoted Intermolecular Enyne Metathesis

Article abstract of DOI:10.1021/ol035270b

(Matrix presented) Intermolecular enyne metathesis between functional group-rich alkynes and vinyl ethers was promoted by ethylene cometathesis. The concentration of ethylene was optimized to suppress the competing formation of butadiene through background ethylene metathesis. The role of ethylene appears to be both protective and rate enhancing.

Full text of DOI:10.1021/ol035270b

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3819-3822
Ethylene-Promoted Intermolecular Enyne
Metathesis
Anthony J. Giessert, Nicholas J. Brazis, and Steven T. Diver*
Department of Chemistry, UniVersity at Buffalo, the State UniVersity of New York,
Amherst, New York 14260
diVer@nsm.buffalo.edu
Received July 9, 2003
ABSTRACT
Intermolecular enyne metathesis between functional group-rich alkynes and vinyl ethers was promoted by ethylene cometathesis. The
concentration of ethylene was optimized to suppress the competing formation of butadiene through background ethylene metathesis. The role
of ethylene appears to be both protective and rate enhancing.
Enyne metathesis is a synthetically useful diene synthesis.1
The cross selectivity of the intermolecular reaction,2 the
functional group tolerance of the ruthenium carbenes, and
increasingly challenging synthetic applications have elevated
the utility of enyne metathesis. In several instances, previous
shortcomings have been surmounted by the use of the more
reactive second-generation Grubbs catalyst. In the course of
studying intermolecular enyne metatheses with vinyl ethers,
we found that certain alkynes failed to react using the carbene
complex 3. We surmised that the generated ruthenium
Fischer carbenes 6 were too unreactive with these more
functional group-rich alkyne substrates. In this report, we
describe the use of ethylene as a helping alkene to promote
reactivity in intermolecular (cross) enyne metathesis, thereby
increasing the applicability of the intermolecular reaction to
problematic substrates (eq 1).
and co-workers3 suggested that the influence of ethylene was
to prevent side reactions of the vinyl carbene species and
would open up degenerate reactions of the active ruthenium
methylidene that would prevent catalyst decomposition and
other mischief.
Scheme 1. Ethylene-Promoted Cross Enyne Metathesis
Ethylene has been used to promote catalyst longevity in
ring-closing enyne metathesis. Mori demonstrated the useful-
ness of ethylene in ring-closing metathesis, a result that has
been widely embraced in the field, especially for difficult
ring-closing metatheses.3 Poor reactivity was overcome by
conducting the reaction under an ethylene atmosphere. Mori
Use of ethylene to promote or influence the course of cross
metathesis is expected to be problematic due to competitive
(1) Reviews: (a) Mori, M. Top. Organomet. Chem. 1998, 1, 133-154.
(b) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1-18.
(2) Stragies, R.; Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2518-2520.
(3) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082-6083.
10.1021/ol035270b CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/20/2003

ethylene metathesis.4 The competing metathesis with ethylene
would produce a butadiene byproduct, but this is largely
suppressed in R,ω-enynes undergoing ring-closing metathesis
since intramolecularity provides a rate advantage. Mori and
co-workers indeed found competitive cross metathesis in
more difficult ring closure en route to medium rings.5 In an
eight-membered ring closure, the butadiene was the major
product.5b Entropic penalties in the ring closure permitted
competitive intermolecular metathesis with ethylene. From
these studies, it was not evident that an alkyne would be
able to selectively react with one alkene over ethylene in an
intermolecular enyne metathesis. Recent work by Lee et al.
illustrates an influence of ethylene on selectivity of cross
enyne metathesis.6
In fact, Fischer carbenes of ruthenium are known to
decompose thermally.9 The propargyl derivative 1A is not
sensitive to thermal elimination of thiol benzoic acid, so
higher temperatures were explored in this case. For cheap
enol ethers, large excesses (25 equiv) can be employed in
benzene to achieve quantitative conversion (entry 5). With
the butynyl derivative 1B, poor conversion was observed in
CH2Cl2 at room temperature (entry 6) and moderate conver-
sion at reflux. The room temperature reaction in benzene
using 25 equiv of EVE gave only 45% conversion in this
case. Monitoring the reaction after 15 h up until 36 h revealed
no further conversion, hinting that catalyst decomposition
had occurred. Large excesses of EVE proved to be successful
in one case, but not the other (entries 5 vs 8). Looking ahead
to future applications where the enol ether must be synthe-
sized, large molar excesses of enol ether would be impractical
and wasteful. We wanted to improve the reliability of the
cross metathesis with respect to various troublesome alkynes
and to determine whether a sacrificial, auxiliary alkene could
be used in place of large molar excesses of enol ethers.10
Ethylene proved to be helpful to the representatively
difficult cross metatheses of eq 2. The use of ethylene as a
co-added alkene seemed attractive due to its low cost and
ease of removal. With two competing alkenes, two different
cross metatheses are possible. Perceiving this difficulty, we
comparatively evaluated the molar ratios of enol ether to
ethylene to minimize the butadiene formed through competi-
tive ethylene-alkyne metathesis. The data are presented in
Table 2. At the highest ethylene pressure investigated, the
amount of butadiene was surprisingly low (entries 1-3).11
Increasing the mole fraction of enol ether (vs total alkene)
reduced the butadiene 7 by a factor of 2. At equilibrium, 60
psig ethylene corresponds to a solution concentration of ca.
0.77 M.12 At lower ethylene pressure, 4-6% of 7 was
observed (entries 4-6). Lower pressure in benzene (PhH)
gave only the dienol ether 2A (entry 7), though fewer
equivalents of enol ether gave about 5% undesired butadiene
(entry 8). The preformed Fischer carbene initiated the
reaction, giving 67% conversion after 24 h. The Hoveyda
catalyst13a,b produced quantitative conversion, although
Grubbs’ pyridine solvate13c gave only 54% conversion,
probably due to aminolysis of the thiol ester by liberated
3-bromopyridine and catalyst poisoning (entries 10, 11).
Lower catalyst loading was not sufficient to obtain syntheti-
cally useful conversions (entries 12, 13). Dichloromethane
was equally effective as a solvent with 9 equiv of enol ether
(entry 14 vs entry 8). Balloon ethylene pressure can be used
with better results in benzene than dichloromethane (entries
15, 17), but 9 equiv of EVE in benzene gives only partial
conversion at balloon ethylene pressure (entry 16).
Thiol benzoates proved to be difficult alkyne players in
the cross metathesis with vinyl ethers.7 Since we felt that
these represented a challenge that would be characteristic
of functional group-rich alkynes, we investigated the reaction
with ethyl vinyl ether (EVE) in detail (Table 1). The same
Table 1. Difficult Cross Metathesis
entry alkyne
x
solvent
CH2Cl2
25 CH2Cl2
conversion (%) time (h)
1
2
3
4
5
6
7
8
1A
1A
1A
1A
1A
1B
1B
1B
9
23a
62a
80a
25
25
9
9
9
PhH
PhH, reflux
100
100
10a
46a
45a
20
18
25
20
15
25 PhH
9
9
CH2Cl2
CH2Cl2, reflux
25 PhH
a Average of two runs.
long reaction times that gave quantitative conversion in the
ethylene metathesis studied previously8 gave only low
conversion in CH2Cl2 using excess EVE (entries 1, 2). Room-
temperature reactions in benzene gave incomplete conver-
sion, but at reflux quantitative conversion to the cross product
occurred (entry 4). The long reaction times were considered
problematic since catalyst longevity would be threatened.
(4) (a) Kinoshita, A.; Sakakibara, N.; Mori, M. J. Am. Chem. Soc. 1997,
119, 12388-12389. (b) Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron
1999, 55, 8155-8167. (c) Smulik, J. A.; Diver, S. T. J. Org. Chem. 2000,
65, 1788-1792. (d) Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271-
2274. (e) Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002, 43, 2235-2238.
(5) (a) Mori, M.; Kitamura, T.; Sakakibara, N.; Sato, Y. Org. Lett. 2000,
2, 543-545. (b) Mori, M.; Kitamura, T.; Sato, Y. Synthesis 2001, 654-
664.
(9) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153-2164.
(10) Difficult metatheses have been repeated using at least two separate
batches of second-generation catalyst.
(11) Fewer equivalents of enol ether and ethylene pressure (60 psig or
higher) produced a greater proportion of the butadiene.
(12) Measured by NMR in CD2Cl2 versus mesitylene as an internal
standard.
(13) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168-8179. (b) Gessler, S.; Randl, S.; Blechert,
S. Tetrahedron Lett. 2000, 41, 9973-9976. (c) Love, J. A.; Morgan, J. P.;
Trnka, T. M.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 4035-4037.
(6) Lee, H.-Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5, 1855-
1858.
(7) Under previously reported conditions, these alkynes either did not
react or decomposed. See: Giessert, A. J.; Snyder, L.; Markham, J.; Diver,
S. T. Org. Lett. 2003, 5, 1793-1796.
(8) Smulik, J. A.; Giessert, A. J.; Diver, S. T. Tetrahedron Lett. 2002,
43, 209-211.
3820
Org. Lett., Vol. 5, No. 21, 2003

Table 2. Ethylene-Assisted Vinyl Ether Cross Metathesis
Table 3. Scope of Co-Enyne Metathesis
conversion
entrya
x
y (psig)
solvent
ratio
(%, at t(h))
1
2
3
4
5
6
7
8
9b
10c
11d
12e
13f
14
15
16
17
9
60
60
60
10
10
10
5
5
5
5
5
5
5
5
g
g
g
CH2Cl2
CH2Cl2
PhH
CH2Cl2
CH2Cl2
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
CH2Cl2
CH2Cl2
PhH
15:100
8:100
6:100
7:100
6:100
4:100
-:100
6:100
-:100
-:100
-:100
1:100
-:100
3:100
-:100
-:100
-:100
100, 20 h
100, 20 h
100, 20 h
82, 20 h
100, 20 h
100, 20 h
100, 20 h
100, 20 h
67, 24 h
100, 24 h
54, 24 h
22, 20 h
22, 20 h
96, 20 h
52, 24 h
44, 24 h
100, 6 h
25
25
9
25
25
25
9
9
9
9
9
9
9
25
9
25
PhH
a Reactions in entries 1-14 were conducted in a Fisher-Porter bottle at
the indicated ethylene pressure. b Performed with 5 mol % 6. c Performed
with 5 mol % 4. d Performed with 5 mol % 5. e Performed with 1 mol %
3. f Performed with 2.5 mol % 3. g Performed with balloon ethylene.
Butadiene 7, obtained from ethylene metathesis, is not an
intermediate en route to dienol 2A. Isolated butadiene 7 was
subjected to two sets of conditions to evaluate its kinetic
stability under the reaction conditions. Heating 7 in benzene
with 3 and 9 equiv of EVE gave no reaction. Similarly, the
cometathesis employing EVE (9 equiv) and ethylene (5 psig)
gave no conversion after 12 h at room temperature. The
kinetic stability of butadienes has been previously observed
by Blechert using the first generation Grubbs catalyst;14
however, Lee et al.6 showed that a 1,3-butadiene will react
with excess 1-alkene with catalyst 3, and we have made
similar observations with 1-hexene. In the present case, it is
likely that the Fischer carbene is not sufficiently reactive to
add to the diene terminus.
a Standard conditions: catalyst 3 (5 mol %), vinyl ether (9 equiv),
ethylene (5 psig), benzene, rt, 12 h. b Yield without ethylene, ratio of (E)-
and (Z)-isomers. c Conversion, 24 h reaction time. d Conversion ) 99%.
e Conversion by NMR after an additional 2.5 mol % catalyst 3 was added.
and decompose on heating. The homopropargylic coordinat-
ing ethers of entries 7-9 give excellent results. Butynyl
benzoate 20 reacts with EVE without ethylene, but vinyl
benzoate, (tert-butyldimethylsilyloxy)ethylene, and tert-butyl
vinyl ether benefit from ethylene (see right column of Table
3) and provide synthetically useful results only by comet-
athesis. Symmetrical internal alkynes react with enol ethers
and do not require the assistance of ethylene.7 As is typical
for the cross enyne metathesis, the products were obtained
as E/Z mixtures; the lack of stereocontrol is apparent in both
the ethylene-promoted reaction and the nonethylene reac-
tions.
The presence of ethylene increases the lifetime of the
Fischer carbene complex. In the absence of ethylene, Fischer
carbene 6 is completely decomposed after 24 h at room
temperature. When the same experiment was conducted
under ethylene, the orange color of the Fischer carbene
persisted for several days. Proton NMR indicated the
The scope of the ethylene-assisted cross enyne metathesis
is summarized in Table 3. The elimination-prone thiol
benzoate 8 decomposes on heating, conditions previously
needed to react enol ethers with alkynes.7 Cometathesis with
ethylene permits the reaction to be conducted at ambient
temperature and gave quantitative conversion (91% yield,
entry 1). Both enol ethers and enol acetates produce the cross
products in excellent yields with the propargylic thiol
benzoates. Besides increased alkyne scope for the enol ether
cross metathesis, silyl enol ethers are shown to react under
the cometathesis conditions (entries 6, 10, 12). The reactions
are notable because the reactions fail without ethylene present
(14) Ruckert, A.; Eisele, D.; Blechert, S. Tetrahedron Lett. 2001, 42,
5245-5247.
Org. Lett., Vol. 5, No. 21, 2003
3821

persistence of 6 over this period. After 48 h, 60% of the
Fischer carbene 6 was still present. Thus, the role of ethylene
may be as simple as stabilizing the Fischer carbene complex,
such that its decomposition rate is reduced sufficiently for
sustainable catalysis at room temperature, where the rate of
reaction is relatively slow (compared to the rate in refluxing
benzene).7 This converges with the proposition of Mori,3
based on observations in ring-closing enyne metathesis with
the first generation Grubbs carbene.
lower path, Scheme 2). This explains why, to a rough
approximation, high concentrations of enol ether duplicate
the effect of co-added ethylene.
Additional experiments are required to test these mecha-
nistic proposals, but they provide a reasonable explanation
for catalysis. The notion that ruthenium methylidene is the
reactive carbene and that increased ethylene pressure provides
a higher concentration of the methylidene C as the active
catalyst cannot be ruled out.
Synthetically, the cometathesis provides access to 3-sub-
stituted furans through simple oxidative transformation with
singlet oxygen. The cycloaddition occurs in good yield, and
peroxyacetal 24 can be isolated and fully characterized.
Reduction with zinc dust and 2 equiv of acetic acid provided
furan 25 in high yield.
The interaction of a 14-electron Fischer carbene intermedi-
ate with ethylene would likely lead to formation of the
methylidene, but this has not been observed by NMR under
various ethylene pressures. While this observation does not
rule out a methylidene mechanism, it does suggest that the
Fischer carbene is considerably more stable than the meth-
ylidene.9 With respect to catalysis, the equilibrium with
ethylene to provide the methylidene may be substantially
uphill (eq 4, Scheme 2). In contrast, alkyne binding and
Scheme 3. Oxidative Transformation of Co-metathesis Product
Scheme 2. Important Equilibria in the Co-Enyne Metathesis
In conclusion, the use of ethylene to overcome unreactive
or poorly reactive alkynes in intermolecular enyne metathesis
with enol ethers is reported. The use of a co-added alkene
to improve the efficiency of the metathesis without significant
competing intermolecular ethylene-alkyne metathesis was
surprising. The role of ethylene appears to be protective and
may assist in methylene transfer, thereby helping catalyst
turnover. Further exploration of these issues and studies on
the reaction mechanism are ongoing in our labs.
Acknowledgment. The authors thank Bryan Schertzer for
measurements of solution concentration of ethylene and Dr.
Alice Bergman (UB Instrumentation Center) for assistance
with mass spectra. We gratefully acknowledge the National
Cancer Institute (R01CA090603) for financial support of this
work.
Supporting Information Available: Experimental pro-
cedures and full characterization data for compounds 2A,
2B, 9-12, 14, 16, 18, 19, and 21-25. This material is
available free of charge via the Internet at http://pubs.acs.org.
conversion to the vinyligous Fischer carbene is roughly
isoenthalpic on the basis of carbene stability alone (eq 5).
On the basis of this hypothesis, the role of ethylene, while
certainly protective, may also accelerate catalyst turnover
by providing an alternate methylene transfer path (panel b,
OL035270B
3822
Org. Lett., Vol. 5, No. 21, 2003