Atom economy in the metathesis cross-coupling of alkenes and alkynes

Article abstract of DOI:10.1021/ol200914j

A cross ene-yne metathesis has been achieved at a nearly 1:1 stoichiometry of the unsaturated reactants. This allowed the use of more complex alkene reactants without sacrificing excess alkene reactant. In the alkene, different allylic oxygen protecting groups were explored. Interestingly, alkenes containing the allylic hydroxyl group proved to be the most reactive.

Full text of DOI:10.1021/ol200914j

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2896–2899
Atom Economy in the Metathesis
Cross-Coupling of Alkenes and Alkynes
Joseph R. Clark and Steven T. Diver*
Department of Chemistry, University at Buffalo, The State University of New York,
Amherst, New York 14260, United States
diver@buffalo.edu
Received April 7, 2011
ABSTRACT
A cross ene-yne metathesis has been achieved at a nearly 1:1 stoichiometry of the unsaturated reactants. This allowed the use of more complex
alkene reactants without sacrificing excess alkene reactant. In the alkene, different allylic oxygen protecting groups were explored. Interestingly,
alkenes containing the allylic hydroxyl group proved to be the most reactive.
Ene-yne metathesis has the potential to be a practical
and efficient carbonÀcarbon cross-coupling.1 In general,
Scheme 1. Ene-Yne Metathesis: A Cross-Coupling of Unacti-
vated Substrates
metal-catalyzed cross-couplings are considered the most
powerful and efficient ways to make carbonÀcarbon
bonds. Yet direct cross-couplings require functional
groups which activate the substrates, after which they are
discarded as byproducts (Scheme 1, eq 1).2 Ene-yne meta-
thesis does not require activation by preexisting CÀX or
CÀY bonds (eq 2). Since there are no activating groups,
ene-yne metathesis does not form byproducts. However,
the major limitation of ene-yne cross metathesis has been
the need to use a large excess of the alkene reactant. Mecha-
nistic work with the second generation Grubbs catalyst 1
explains why higher alkene concentrations are beneficial.3
In this Letter, we report a truly atom economical4 ene-yne
cross metathesis as a practical, metal-catalyzed cross-
coupling.
A large excess of alkene reactant and lack of knowledge
of substrate reactivity limit ene-yne metathesis as a pre-
dictable cross-coupling. Moreover, ene-yne cross metathesis
kinetic studies have been performed over a limited range
of substrates.5 With catalyst 1, the slow step involves
the alkene, so alkene concentration is a critical reaction
variable. With catalyst 2, higher alkene concentrations
(1) Recent reviews: (a) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004,
104, 1317–1382. (b) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1–18. (c)
First ene-yne cross metathesis: Blechert, S.; Stragies, R.; Schuster, M.
Angew. Chem., Int. Ed. 1997, 36, 2518–2520.
(2) A survey of recent synthetic applications of the Suzuki coupling
shows that either the vinyl halide or organoborane may be used in
1.3À1.5 molar excess of the limiting reagent. Similarly, between 5 and
15 mol % Pd catalyst is commonly used.
(3) For Grubbs’ carbene complex 1, the rate dependence on [alkene]
indicates that it is involved in the slow step in the catalytic cycle.
(4) Trost, B. M. Science 1991, 254, 1471–1477.
(5) Using the second generation Grubbs complex: (a) Galan, B.;
Giessert, A. J.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2005, 127,
5762–5763. Using the first generation Grubbs complex: (b) Marshall,
J. E.; Keister, J. B.; Diver, S. T. Organometallics 2011, 30, 1319–1321. (c)
The kinetics of ene-yne metathesis promoted by phosphine-free carbenes
has not, to our knowledge, been studied.
r
10.1021/ol200914j
Published on Web 05/11/2011
2011 American Chemical Society

were found to limit a competing pathway that led to
catalyst decomposition,6 though kinetic studies are lacking
with this catalyst.5c By far, the most common alkene
reactants are simple 1-alkenes; in these cases large excesses
are reasonable. However, the perceived need to use a large
excess of the alkene reactant limits the use of ene-yne
metathesis with complex substrates. CarbonÀcarbon cou-
pling achieved by the metathesis could be used as a
fragment coupling to join two complex pieces in a total
synthesis. The functional group tolerance of the Grubbs
catalyst and the catalytic nature of ene-yne metathesis
makes alkene-alkyne fragment coupling appealing. How-
ever, a notable attempt to use ene-yne cross metathesis as a
fragment coupling in a complex molecule synthesis failed
despite a screen of reactants and conditions.7 This litera-
ture example illustrates the need for an improved under-
standing of the reaction before it can be reliably used in
synthesis.8 Our study was motivated by the need to better
understand critical reaction variables in order to guide the
successful use of cross ene-yne metathesis in complex
molecule assembly. Ideally, alkyne and alkene would be
combined in a 1:1 stoichiometry, minimizing the need to
use an excess of a potentially precious alkene.
Screening catalyst and reaction conditions led to opti-
mized reaction conditions with equimolar concentrations
of alkyne and alkene reactants (Table 1). A key insight was
obtained from previous studies in our group where tem-
perature was found to play a critical role in achieving a
rapid intermolecular reaction.9 At 60 °C in DCE, complete
conversion of alkyne was observed under nominal concen-
trations of the reactants (0.05À0.08 M alkyne). At these
temperatures, an isomerized product 6 was found in 10%
yield (entry 1); an extended reaction time resulted in an
increased amount of 6 at the expense of the Z-isomer,
which was not detected at all (entry 2). Using the triphe-
nylphosphine Grubbs complex 3, very similar results were
obtained compared to the case using complex 1(entry3vs1).
Though lower reaction temperatures necessitated longer
reaction times for full conversion of alkyne, these condi-
tions successfully eliminated the byproduct in either DCE
or toluene (entries 4, 5). At elevated temperature, benzo-
quinone (BQ) was used as a coadditive. Inclusion of BQ
prevented byproduct formation, allowing shorter reaction
times at 60 °C (entry 6). Benzoquinone had been used
previously by Grubbs to suppress alkene isomerization, a
process which was thought to occur due to a ruthenium
Table 1. Screening Results
1
a ’nd’ = not detected by H NMR spectroscopy; BQ = benzoqui-
none. b Incomplete conversion of alkyne was observed.
hydride species formed in situ.10 Our decision to use BQ as
an additive was also based on the known conversion of
ruthenium carbenes to ruthenium hydrides in the presence
of alcohols.11 Proton NMR monitoring did not detect any
upfield proton resonances in the catalyst itself (before the
reaction) or in the crude reaction mixture.12 Continued
catalyst screening showed that the bis tolyl HoveydaÀ
Grubbs carbene 4 was less effective, with incomplete
consumption of the alkyne (entries 7, 8). Shorter reaction
times and complete conversions were obtained using com-
plex 2 in DCE or benzene solvents, though 6 was still a
significant byproduct (entries 9, 10). At higher tempera-
tures, use of the BQ additive limited byproduct forma-
tion using catalyst 2 (entry 11). In summary, use of BQ
permitted short reaction times with no isomerization to pro-
duct 6 detected. These conditions were adopted as standard
conditions.
A range of alkene-alkyne combinations successfully
underwent enyne metathesis cross-coupling (Table 2).13
R-Substituted alkynes were generally more reactive than
non-R-branched alkynes.14 3-Butynyl benzoate reacted
with a range of 1-alkenes at nearly equimolar ratios
(entries 1À6). If there was no free hydroxyl group in the
alkene reactant, then benzoquinone was not used as an
(10) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160–17161.
(6) Diver, S. T.; Kulkarni, A. A.; Peppers, B. P.; Clark, D. A. J. Am.
Chem. Soc. 2007, 129, 5832–5833.
(7) Nicolaou, K. C.; Brenzovich, W. E.; Bulger, P. G.; Francis, T. M.
(11) (a) Dinger, M. B.; Mol, J. C. Organometallics 2003, 22, 1089–
1095. (b) 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, 2546–2558. (c) Louie, J.; Bielawski, C. W.;
Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312–11313.
(12) Prepurified catalyst (as in Sutton, A. E.; Seigal, B. A.; Finnegan,
D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390–13391) gave
similar results.
Org. Biomol. Chem. 2006, 4, 2119–2157.
(8) There are a few examples of ene-yne cross metathesis in synthesis,
though these are not used as fragment couplings, and the alkene was
used in molar excess (2.4À10 equiv): (a) Ko, H. M.; Lee, C. W.; Kwon,
H. K.; Chung, H. S.; Choi, S. Y.; Chung., Y. K.; Lee, E. Angew. Chem.,
Int. Ed. 2009, 48, 2364–2366. (b) Kim, C. H.; An, H. J.; Shin, W. K.; Yu,
W.; Woo, S. K.; Jung, S. K.; Lee, E. Angew. Chem., Int. Ed. 2006, 45,
8019–8021. (c) Watanabe, K.; Minato, H.; Murata, M.; Oishi, T.
(13) Benzoquinone is included only for alkene reactants bearing free
hydroxyl groups, e.g. allylic alcohols.
€
Heterocycles 2007, 72, 207–212. (d) With ethylene: Furstner, A.;
(14) Our previous rationale for the effect using Grubbs carbene 1 was
a phosphine-bound resting state which was destabilized by R-substitu-
tion resulting in a higher active catalyst concentration. In the present
case without phosphine, there is no tricyclohexylphosphine-bound
resting state, so the effect of R-substitution is different with catalyst 2.
€
Larionov, O.; Flugge, S. Angew. Chem., Int. Ed. 2007, 46, 5545–5548.
(e) For intramolecular examples, please see ref 1a.
(9) Clark, D. A.; Clark, J. R.; Diver, S. T. Org. Lett. 2008, 10, 2055–
2058.
Org. Lett., Vol. 13, No. 11, 2011
2897

additive. Interestingly, the E/Z ratios were dependent on
the 1-alkene (cf. entry 3 or 4). A bulky TBS substituent gave
lower chemical yields (entry 7), but R-branching in combi-
nation with an R acyloxy group proved to be good partners
in the coupling (entries 8À10). In each of these cases, the
BQ additive was used to suppress isomerization byproduct
formation. For alkynes without R-branching the yields
were slightly lower (entries 11À13). From these studies,
propargylic ester protecting groups emerge as an excellent
choice for protection of propargylic hydroxyl groups.
coupling of the Evans aldol product 22 with alkyne 24 gave
E-27 in good yield; similarly, coupling with alkyne 23 gave
E-28 in 46% yield. The propargylic benzoate proved to be
the best protecting group for propargylic alcohols under
these coupling conditions.
Although the yields in Table 2 are generally very good,
we investigated whether the conversions could be pushed
further. Reaction monitoring by 1H NMR revealed a very
fast cross ene-yne metathesis coupling followed by slow
degradation of the alkyne reactant. Most likely, this rapid
halt to alkene conversion is a result of catalyst decomposi-
tion. To increase the conversion of alkyne, the usual
approach would be to increase the alkene concentration
to keep the carbene active in the catalytic cycle, and
possibly to thwart competing pathways.6 Interestingly,
efforts to increase the yield by increasing the equivalents
of alkenol reactant did not help: Using Grubbs’ catalyst 1,
alkyne 24reacted with1.2 equiv of 21A togive E-25in 30%
yield (1H NMR versus mesitylene internal standard, ben-
zene, rt, 24 h); with 2.0 equiv of 21A, the same yield was
observed after the same time under identical conditions
Table 2. Atom Economy in Ene-Yne Metathesis Cross-
Coupling
˚
(Scheme 2). At higher temperatures (1,2-DCE, 60 C)
using HoveydaÀBlechert complex 2, 70% conversion to
E-25 was obtained after 15 min; with 2 equiv of 21A, 70%
conversion was also obtained after this time and the reaction
did not proceed to significantly higher conversion on further
reaction monitoring. It is likely that the allylic alcohol offers
the best match from a reactivity standpoint, but that ruthe-
nium carbene decomposition is also occurring by a compe-
titive reaction. It should also be noted that the phosphine-
free HoveydaÀBlechert carbene 2may show different alkene
rate dependency as compared to Grubbs catalyst 1; this has
not been studied for ene-yne metathesis.5c,16,17
Scheme 2. Cross-Couplings with Functionalized Reactants
a Conditions: 1.0 equiv of alkyne, 1.2 equiv of alkene, 1 or 2 (10 mol %)
in 1,2-DCE at the specified temperature for 0.5À2.0 h. Isolated yields are
reported. b Using Grubbs carbene 1. c Using HoveydaÀBlechert carbene
2. d Using 10 mol % benzoquinone.
Using the standard conditions from Table 2, alkenes and
alkynes of similar complexity were coupled in equimolar
amounts. During this study, particular functionality in the
allylic position proved detrimental: alkenes 21B and 21C
failed to react with alkyne 23 under optimized conditions.
These protecting groups are not recommended and help
explain the poor reactivity observed by Nicolaou et al.7
For allylic alcohol derivatives, the free hydroxyl performed
the best, most likely due to lesser steric hindrance.15 As a
result, fragment couplings could be carried out in reason-
able yields under catalytic conditions. The unprotected
syn-aldol 21A gave efficient cross ene-yne metathesis with
alkynes 24 and 23 to give the respective dienes E-25 and
E-26, each obtained asthe pure E-isomer. Cross metathesis
The stoichiometric equivalency and efficiency of the
cross-coupling permits use of a bifunctional alkene sub-
strate for a two-directional synthesis.18 Normally this
(16) The rate-determining step for alkene metathesis depends on
alkene concentration for Hoveyda-type catalysts: (a) Gatti, M.;
Vieille-Petit, L.; Luan, X.; Mariz, R.; Drinkel, E.; Linden, A.; Dorta,
R. J. Am. Chem. Soc. 2009, 131, 9498–9499. (b) Kuhn, K. M.; Bourg, J.-
B.; Chung, C. K.; Virgil, S. C.; Grubbs, R. H. J. Am. Chem. Soc. 2009,
131, 5313–5320. (c) Vorfalt, T.; Wannowius, K.-J.; Plenio, H. Angew.
Chem., Int. Ed. 2010, 49, 5533–5536.
(17) Efforts to identify the byproduct were unsuccessful.
(18) (a)Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc.
1987, 109, 1525. (b) Poss, C.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9.
(15) (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123. (b) Michaelis,
S.; Blechert, S. Org. Lett. 2005, 7, 5513.
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Org. Lett., Vol. 13, No. 11, 2011

would not be possible since the alkene is used in large excess,
preventing double substitution of a diene reactant. Divinyl
carbinol was reacted with a 2-fold excess of alkyne, to give
the tetraene 29 in 27% isolated yield. The low yield is due to
the sensitivity of the tetraene and the result of two modest
yielding cross ene-yne metathesis steps (representative yields
can be found in Table 2). With tetraene 29 in hand, a site-
selective desymmetrization using the Sharpless conditions
provided the chiral epoxide 30 in good yield (58% yield, 9:1
dr; 92% ee-chiral HPLC, Scheme 3).
In conclusion, a highly efficient ene-yne metathetical
cross-coupling has been achieved. Our studies with more
complex alkene reactants revealed shortcomings that ex-
plain a previously failed metathesis, and we identified the
best combination for an atom-economical cross-coupling.
A better picture of substrate reactivity is emerging, and we
expect these data to be useful in the planning of complex
molecule synthesis where metathesis will be employed as a
fragment coupling strategy. Further studies into the cata-
lytic mechanism and applications to total synthesis are
ongoing in our laboratories.
Acknowledgment. We thank Mr. Jordan Sumliner
(NSF-REU student participant Summer 2009, CHE-
0851700) for preliminary studies with 4-pentenol. The
authors gratefully acknowledge Dr. Richard Pederson of
Materia, Inc. for catalyst support and the NSF (CHE-
0848560) for financial support.
Scheme 3. Double Metathesis Cross-Coupling and Sharpless
Desymmetrization
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is
available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 11, 2011
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