Geminal alkene-alkyne cross metathesis using a relay strategy

Article abstract of DOI:10.1021/ol301846q

A relay strategy was employed to achieve an intermolecular ene-yne metathesis between 1,1-disubstituted alkenes and alkynes. The relay serves to activate an unreactive alkene which will not participate in ene-yne metathesis. The new relay cross ene-yne me

Full text of DOI:10.1021/ol301846q

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4178–4181
Geminal AlkeneÀAlkyne Cross
Metathesis Using a Relay Strategy
Joseph R. Clark, Jonathan M. French, Edgars Jecs, 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 July 5, 2012
ABSTRACT
A relay strategy was employed to achieve an intermolecular eneÀyne metathesis between 1,1-disubstituted alkenes and alkynes. The relay serves
to activate an unreactive alkene which will not participate in ene-yne metathesis. The new relay cross eneÀyne metathesis gives rise to 1,1,
3-trisubstituted-1,3-dienes previously inaccessible by direct eneÀyne metathesis methods.
EneÀyne metathesis has become a useful method for
carbonÀcarbon bond formation, used increasingly in
complex molecule synthesis and with atom economy.1
Mechanistic studies have shown that cross eneÀyne me-
tathesis requires a reactive alkene, capable of initiating
with the ruthenium carbene catalyst. One of the most
significant limitations in the alkene reactant is that posed
by geminal disubstitution. Geminally substituted, or 1,
1-disubstituted, alkenes fail to react with alkynes in eneÀyne
cross metathesis. In this report, we have used the relay
metathesis strategy2 to achieve metathesis reactivity of
geminally substituted alkenes in order to promote inter-
molecular eneÀyne cross metathesis (Scheme 1a). This
work is a unique application of relay metathesis which
serves to expand the breadth of this important concept to
include intermolecular reactions.
Relay metathesis was developed by Hoye and co-workers2
as a means to differentiate the ends of a dienyne (Scheme 1c).
In this case, a relay is used to initiate the cascade, thereby
favoring the formation of one bicyclic product over another.
In intramolecular (i.e., ring-closing) cases, relay metathesis
has emerged as a powerful technology. For instance, in total
synthesis applications of ring-closing metathesis (RCM) the
relay strategy has been used to direct initation to a particular
site.2b,c Applications in cross metathesis are limited.3,4
We wanted to use relay metathesis to overcome
poorly reactive alkenes for use in cross eneÀyne metathesis.
(3) Relay RCM has been elegantly used in mechanistic studies
involving metallotropic shift, which was subsequently followed by a
cross alkene metathesis; see: Cho, E. J.; Lee, D. Org. Lett. 2008, 10, 257–
259.
(4) In one case, we observed a relay closure and cross eneÀyne
metathesis in the same step: Clark, J. R.; French, J. M.; Diver, S. T.
J. Org. Chem. 2012, 77, 1599–1604.
(5) There is only one example that we are aware of: (a) Watanabe, K.;
Minato, H.; Murata, M.; Oishi, T. Heterocycles 2007, 72, 207–212.
Using strain: (b) Clark, D. A.; Basile, B. S.; Karnofel, W. S.; Diver, S. T.
Org. Lett. 2008, 10, 4927–4929.
(6) Geminal alkenes will give ring-closing (i.e., intramolecular) enyne
metathesis with the right choice of catalyst; see: (a) Michrowska, A.;
Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am.
Chem. Soc. 2004, 126, 9318–9325. (b) Boeda, F.; Clavier, H.; Nolan, S. P.
Chem. Commun. 2008, 2726–2740. For macrocyclization enyne metath-
esis benefits from relay assistance, see: (c) Zakarian, J. E.; El-Azizi, Y.;
Collins, S. K. Org. Lett. 2008, 10, 2927–2930.
The relay metathesis strategy has not been used to
overcome a substrate limitation in eneÀyne metathesis.
(1) Enyne reviews: (a) Poulsen, C. S.; Madsen, R. Synthesis 2003,
1–18. (b) Mori, M. Ene-Yne Metathesis. In Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vol. 2, pp 176À204.
(c) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317–1382. (d)
Diver, S. T. Sci. Synth. 2009, 46, 97–146. (e) Ring-closing enyne
metathesis: Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev. 2007, 36,
55–66.
(2) (a) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao,
H. J. Am. Chem. Soc. 2004, 126, 10210–10211. (b) Hoye, T. R.; Jeon, J.;
Kopel, L. C.; Ryba, T. D.; Tennakoon, M. A.; Wang, Y. Angew. Chem.,
Int. Ed. 2010, 49, 6151–6155. (c) Hoye, T. R.; Jeon, J. In Metathesis in
Natural Product Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: 2010;
p 261.
(7) The Grubbs model for cross alkene metathesis predicts poor
initiation reactivity of geminal alkenes; see: Chatterjee, A. K.; Choi,
T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125,
11360–11370.
r
10.1021/ol301846q
Published on Web 08/06/2012
2012 American Chemical Society

Table 1. Optimization of the Relay Cross EneÀYne Metathesis
Scheme 1. The Relay Approach in Cross EneÀYne Metathesis
for Unreactive Geminally Substituted Alkenes
Ru
equiv time
yield
by-
entry (mol %)
1
(h)
additive
2a product
1
Ru1 (10)
Ru1 (10)
Ru2 (10)
Ru1 (5)
1
1
1
1
1
none
none
none
none
52%
48%
48%
73%
83%
73%
75%
20%
9%
18%
0%
0%
0%
0%
0%
2b
3
1.5
1.5
6
4c
5
Ru1 (7.5)
Ru1 (7.5)
Ru1 (7.5)
Ru1 (7.5)
2
0.5 BQ (10 mol %)
0.5 none
6
2
7
2
0.5 BQ (25 mol %)
8
2
0.5 Cl4BQ (10 mol %) 76%
a NMR yield determined by integration vs mesitylene internal stan-
dard. b Entry 2 was run in toluene. c Entry 4 had 10% unreacted alkyne.
Geminally-substituted alkenes fail to give cross eneÀyne
metathesis.5À7 The mechanism of eneÀyne metathesis8 re-
quires that the alkene react with the Grubbs catalyst to form
an alkylidene. If the alkylidene cannot form, then the catalytic
eneÀyne metathesis cannot proceed. The relay metathesis
offers a potential solution if it can be used to direct carbene
formation to an unreactive site and avert the formation of
side products.9
The relay cross eneÀyne metathesis was evaluated using
different conditions in an effort to identify the optimum
reaction conditions (eq 1). A significant concern was the
number of equivalents of the relay substrate;too much
could lead to cross eneÀyne metathesis before RCM.10
The optimization of reaction conditions is summarized in
Table 1. As a starting point, it was discovered that the
HoveydaÀGrubbs catalyst (Ru1) gave the relay ring-
closing metathesis/cross eneÀyne metathesis product in rea-
sonable yield. Due to its volatility, the dihydrofuran was
not observed after isocyanide quenching11 and evaporative
removal of volatiles. At higher temperatures, a byproduct
was formed in significant amounts (eq 1). Increasing 1 had
a negligible effect on yield. In entry 3, the Grubbs catalyst
Ru2 gave similar results as those obtained with Ru1. A
decrease in catalyst loading and increase in alkene equiva-
lents gave a reaction at rt, although it did not go to
completion after a period of 1 h (entry 4). Shorter reaction
times were favored because greater catalyst decomposition
was expected after prolonged heating. The byproduct is
thought to arise from a ruthenium hydride species gener-
ated in situ by catalyst decomposition.12 Since fewer
equivalents of 1 resulted in byproduct formation, we
sought to accelerate the cross metathesis by using 2 equiv
of 1 and to suppress the byproduct by use of 1,4-benzo-
quinone (BQ) as an additive. The use of BQ suppressed
byproduct formation and was used to vouchsafe the 1,3-
diene formed by the tandem relay ring-closing/cross eneÀ
yne metathesis. Comparison of entries 5 and 6 show that
inclusion of benzoquinone has a slightly beneficial effect
on chemical yield. A further increase in the amount of BQ
did not improve the yield (entry 7) nor did tetrachloro-
benzoquinone (entry 8). The conditions in entry 5 were
adopted as the standard conditions. Additional catalysts
were screened, but none were found to be superior to the
HoveydaÀGrubbs catalyst when considering the short
reaction time.
(8) Galan, B. R.; Giessert, A. J.; Keister, J. B.; Diver, S. T. J. Am.
Chem. Soc. 2005, 127, 5762–5763.
(9) Potential side reactions include cross eneÀyne metathesis prior to
relay ring-closing metathesis (giving i), poor cross selectivity (alkene vs
alkyne, giving ii), and competing alkene isomerization.
The relay-triggered delivery of geminal alkylidenes was
found to be useful for a range of alkynes (Table 2). Using
the optimized conditions found in Table 1, the cross
eneÀyne metathesis proceeded in good yield as evident
1
from the crude H NMR taken right after isocyanide
quenching. In the first entry, the produced diene was formed
in 83% yield and trapped by subsequent cycloaddition
(10) Concentration was also optimized.
(11) Isocyanide quenching of metathesis reactions: Galan, B. R.;
Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister, J. B.; Diver, S. T. Org.
Lett. 2007, 9, 1203–1206.
(12) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160–17161.
Org. Lett., Vol. 14, No. 16, 2012
4179

with N-phenylmaleimide. Due to the hydrophobic
nature of the products, their separation from unreacted
excess 1 was sometimes difficult. In those cases, a sub-
sequent deprotection step was used to liberate the
alcohol, which aided the purification step. In these
cases (entries 2, 4, 5), the isolated yield is provided over
two steps. The NMR yield taken after the metathesis
step provides a good indication of the effectiveness of
the metathesis. Branched and linear terminal alkynes
performed equally well in the cross metathesis (entries
1À4). In one case, the reaction of an internal alkyne
gave a lower yield in the metathesis step; the diene
product was characterized after saponification of the
acetates to aid purification from excess 1.
the product was trapped through an in situ thermal
DielsÀAlder reaction giving cycloadduct 14.
Table 3. Cycloalkylidene Transfer by Relay Cross EneÀYne
Metathesis
Table 2. Alkyne Scope Study
a NMR yield after the relay metathesis step. b Isolated yield after two
steps. c Isolated yield after two steps including DielsÀAlder cycloaddi-
tion (PhCH3, 80 °C, 36 h).
Following the cycloalkylidene transfers of Table 3, the
attempted transfer of a cycloheptylidene led to use of an
alternate relay (Scheme 2). Hoye had studied various relay
tethers in his relay ring-closing metathesis reaction, mostly
employing ethers and malonates.2 These were mainly
selected based on synthetic convenience, although Hoye
has noted distinction of the malonate relay tether.13 In our
attempted cycloheptylidene transfers, the ether-containing
tether 15 did not perform well; only 22% of the desired
product was obtained (Scheme 2). The major reaction
pathway was that of cross eneÀyne metathesis, without
the preemptive relay ring closure. This clearly suggested
that the relay was not efficient enough. The malonate
linker 16 was thus prepared and gave a much better yield
of 17. Benzoquinone was included and gave a slight
improvement in chemical yield. The results were compar-
able to that obtained in the more difficult cycloalkylidene
transfers of Table 3. A strain-driven cyclobutylidene trans-
fer has been previously reported.5b
a NMR yield determined after the relay cross metathesis. b Isolated
yield after DielsÀAlder cycloaddition with N-phenylmaleimide (PhCH3,
80 °C, 72 h). c Isolated yield after two steps.
Next, we consideredrelay cross metathesis asa vehicle to
transfer cycloalkylidenes to external alkynes (Table 3). To
activate these alkenes, an appended exocyclic allyl ether was
required. Substrates 8 and 9 were easily prepared from the
corresponding cycloalkanones by a HornerÀEmmonsÀ
Wadsworth/reduction/allylation sequence which proceeded
uneventfully. In the event, relay cross metathesis worked
efficiently for a range of terminal alkynes (eq 3). Cyclo-
pentylidenes were transferred by eneÀyne metathesis to
branched and unbranched alkynes (entries 1, 2) under the
standard conditions found in Table 1, with 10 mol %
benzoquinone present. Transfer of the cyclohexylidene
proved more difficult (entries 3, 4). Presumably the increased
steric hindrance imposed by the endocyclic allylic hydrogens
(see A) impedes the ring closure step, decreasing the overall
effectiveness of the tandem process. With the last example,
(13) Attributed to better ejection of the bound cycloalkene after the
relay ring closure; see: Hoye, T. R.; Jeon, J.; Tennakoon, M. A. Angew.
Chem., Int. Ed. 2011, 50, 2141–2143.
4180
Org. Lett., Vol. 14, No. 16, 2012

proximal functional groups? Relay alcohol 18 was pre-
pared by a four-step synthetic sequence and isolated as the
E-isomer shown. The relay cross eneÀyne metathesis
proceeded in low yield, giving E-21 in 24% isolated yield
(Scheme 3). Including BQ did not significantly improve the
reaction (data not shown). In the case of the acetate 19, the
chemical yield was significantly improved, and 22 was
obtained as a 1:1 E/Z mixture. Use of the TBS ether could
have impeded the relay ring closure; however it gave the
best yield compared to the relay cross metathesis of 18 and
19. For the allylic silyl ether 20, stericbulkwasnotsufficient
to influence the stereoselectivity of the cross eneÀyne
metathesis. Further substitution at the allylic center may
be needed to obtain stereoselective alkylidene transfers.
In conclusion, the relay metathesis strategy has been
used to promote cross eneÀyne metathesis involving un-
reactive geminal alkene substrates. The relay provides a
gain of alkene reactivity in an alkene substrate that nor-
mally lacks sufficient reactivity for cross metathesis. This
reactivity gain expands thescopeof the intermolecularene-
yne metathesis and elaborates the synthetic potential of the
relay metathesis concept. Simple 1,1-disubstituted alkyli-
denes and cycloalkylidenes can be transferred using simple
relay tethers that are easy to synthesize. Functional group
effects were observed in the alkene undergoing intermo-
lecular transfer. In some cases, higher temperatures re-
sulted in positional isomerization of the 1,3-diene, but this
could be minimized using benzoquinone as an additive.
Scheme 2. Cycloheptylidene Transfer
Scheme 3. Relay Transfer of Unsymmetrical Alkylidenes
Unsymmetrical geminal alkenes fitted with a relay tether
also give cross eneÀyne metathesis. These relay-activated
alkenes were considered to be more difficult due to their
potential to form geometrical isomers. This system was
also used to probe allylic substituent effects in the geminal
alkylidene transfer. In cross metathesis applications, the
allylic substituent has a pronounced effect on reactivity.14
For instance, allylic alcohols are thought to accelerate
initiation of cross metathesis,14aÀc whereas TBS ethers in
the same position tend to retard reaction.14d Would steric
and electronic factors impact the effectiveness of the relay
cross eneÀyne metathesis, when brought to bear on these
Acknowledgment. This work was supported by the Na-
tional Science Foundation (CHE-0848560). J.R.C. ac-
knowledges the SUNY Buffalo Chemistry Department
for award of a Speyer Graduate Fellowship. The authors
are grateful to Dr. Richard Peterson (Materia, Pasadena, CA)
for supplying Grubbs’ catalyst.
Supporting Information Available. Experimental pro-
cedures and full characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123–1125. (b)
Imahori, T.; Ojima, H.; Tateyama, H.; Mihara, Y.; Takahata, H.
Tetrahedron Lett. 2008, 49, 265–268. (c) Clark, J. R.; Diver, S. T. Org.
Lett. 2011, 13, 2896–2899. (d) Michaelis, S.; Blechert, S. Org. Lett. 2005,
7, 5513–5516.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
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