Alkenol alkyne cross metathesis

Article abstract of DOI:10.1021/ol800523j

Allyl alcohols and their homologues were used In the enyne cross metathesis to prepare hydroxy-functionallzed dienes. An isomerization was found to occur under prolonged heating, and a method for conversion to (E)-diene product is also reported.

Full text of DOI:10.1021/ol800523j

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2055-2058
Alkenol-Alkyne Cross Metathesis
Daniel A. Clark, Joseph R. Clark, and Steven T. Diver*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Amherst, New York 14260
diVer@buffalo.edu
Received March 8, 2008
ABSTRACT
Allyl alcohols and their homologues were used in the enyne cross metathesis to prepare hydroxy-functionalized dienes. An isomerization was
found to occur under prolonged heating, and a method for conversion to (E)-diene product is also reported.
Enyne metathesis has become a useful method for diene
synthesis.1 In particular, the cross enyne metathesis between
Scheme 1. Allyl Alcohol-Alkyne Cross Metathesis
an alkene and alkyne is attractive because it joins two simple
unsaturated reactants into a diene building block that can be
employed in further transformation. A major concern in
synthetic applications of metathesis has been the choice of
protecting groups for hydroxyl groups, especially in the
allylic position.2 Oxygen functionality, though tolerated by
the Grubbs ruthenium carbenes, may chelate to the metal
carbene,3 slowing catalysis or resulting in decomposition.
In alkene metathesis, allylic alcohols are tolerated but also
may result in destruction of the metal carbene. We were
interested in incorporating alcohol functionality into the diene
product and wanted to learn whether allylic alcohols posed
difficulties in enyne metathesis. In this report, we show that
free hydroxyl functionality is tolerated in the alkene reactant
in cross enyne metathesis (eq 1 in Scheme 1).
closing alkene metathesis (RCM) with the first generation
Grubbs carbene. At the same time, secondary allylic alcohols,
though they react faster in RCM, also have a decomposition
mechanism available that results in truncation of the unsatur-
ated moiety and its conversion to a methyl ketone (eq 2 in
Scheme 2).5a,b Subsequently, Paquette and Efemrov5b ob-
served the truncation during a “routine” ring-closing alkene
metathesis. Hoye had also found that allylic ethers initiated
more slowly than the corresponding allylic alcohol. Yet in
With no literature on enyne metathesis to guide us, we
looked to previous work in alkene metathesis.4 Hoye and
Zhao5a found that there was an accelerating effect for tertiary
allylic alcohols versus their hydrocarbon analogues in ring-
(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, Germany, 2003; Vol. 2, pp 176-204.
(c) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317–1382.
(2) Gennari summarizes the range of results found in complex molecules:
Caggiano, L.; Castoldi, D.; Beumer, R.; Bayon, P.; Telser, J.; Gennari, C.
Tetrahedron Lett. 2003, 44, 7913–7919.
(4) The mechanistic interpretation of enyne metathesis has been closely
intertwined with that of alkene metathesis. To a first approximation, the
initiation abilities of alkenes will determine their success in either alkene
or enyne metathesis.
(3) (a) Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron 1999, 55,
8155–8167. (b) Kulkarni, A. A.; Diver, S. T. J. Am. Chem. Soc. 2004, 126,
8110–8111.
(5) (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123–1125. (b) Paquette,
L. A.; Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492–4501. (c) Michaelis,
S.; Blechert, S. Org. Lett. 2005, 7, 5513–5516.
10.1021/ol800523j CCC: $40.75
Published on Web 04/15/2008
2008 American Chemical Society

refluxing 1,2-DCE. Similar reaction times were observed with
the Hoveyda-Blechert carbene 2. This proved to be a
remarkably fast intermolecular metathesis, conducted under
the typical conditions using an excess of the alkene reactant.8
After 40 min, the reaction was stopped using the quenching/
clean up protocol developed in our laboratory: addition of
the polar isocyanide 5 (25-50 mol %)9 as a solution in
methanol. The diene 11A was produced in 74% isolated yield
as a 2.5:1 mixture of E/Z isomers.
Scheme 2
.
Decomposition of Secondary Allylic Alcohols (Hoye
and Zhao, 1999)
We systematically examined the effect of distance between
the free hydroxyl group and the alkene (Table 1). We found
that alcohols 8-10 reacted effectively under the normal
reaction conditions. Good isolated yields were obtained in
all cases. Notably, the secondary allylic alcohol 10 (entry
4) performed well under catalytic conditions, suggesting that
carbene decomposition is not a factor in these reactions,
probably due to the catalyst used and the short reaction times.
The scope of the alkenol-1-alkyne cross metathesis is
summarized in Table 2. The usual protecting groups were
complex, highly functionalized dienes, ethers may perform
better than the free alcohol.2 Michaelis and Blechert5c
conducted a selective cross alkene metathesis on dienol 3,
using a trityl group to block reaction on one side. These
investigators attributed the chemoselectivity to steric hin-
drance of the bulky trityl group. Alcohol functionality in
alkene metathesis is of great interest due to the potential to
use aqueous solvents.6 Very recently, Takahata and co-
workers reported an accelerating effect of an allylic hydroxyl
group in a ring-closing enyne metathesis using the first
generation Grubbs carbene.7 In summary, the literature from
olefin metathesis suggests activation of allylic alcohols, but
initiation proximal to a secondary allylic alcohol also
promotes a rearrangement that is fatal to the ruthenium
carbene catalyst. What is the relative significance of these
observations in relation to cross enyne metathesis?
Table 2. Cross Enyne Metathesis with Unsaturated Alcoholsa
We began our studies by examining the cross metathesis
between alkenols and alkyne 6A (eq 3 in Table 1). Under
Table 1. Various 1,ω-Alkenols in Cross Enyne Metathesisa
a Reaction conditions: alkyne (0.2 M), alkene (1.2 M), 1 (5 mol %),
1,2-dichloroethane, reflux, 40 min; isocyanide 5 (25 mol %). b Reaction
performed on 15 mmol scale.
a Reaction conditions: alkyne (0.2 M), alkene (1.2 M), 1 (5 mol %),
1,2-dichloroethane, reflux, 40 min; isocyanide 5 (∼25 mol %).
well tolerated in the propargylic position. In particular, the
alkyl ethers in entries 1 and 2 have potential to chelate to
intemediate carbenes, but they proved reactive. Similar results
were obtained with the silyl protecting groups (entries 3 and
4). A more remote alcohol is also tolerated in the reaction
standard conditions employing 3 equiv of allyl alcohol 7 and
5 mol % of Grubbs’ second generation carbene (complex
1), complete reaction was detected in less than 10 min in
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Org. Lett., Vol. 10, No. 10, 2008

(entry 6). With oxygen functionality in the homopropargylic
position (alkynes 14), the reaction was efficient for a variety
of unsaturated alcohols (allyl alcohol entries 7 and 10; and
homologues entries 8, 9 and 11,12). Slightly poorer yield of
the homologous diene 15E was obtained under the standard
conditions. From entry 13, it can be seen that remote nitrogen
functionality results in modest yields of diene 17.10 However,
these reactions were not reoptimized from the standard
conditions. The simple hydrocarbon 1-octyne performed
acceptably in entry 14.10 The propargyl-substituted substrate
4 (Scheme 2) did not perform well in the metathesis with
allyl alcohol 7 for reasons that are not completely understood.
Last, the metathesis in entry 1 was performed on a 15 mmol
scale, showing that the process is scaleable. In all of these
cases, a mixture of E and Z isomers is obtained.
diene. Heating the reaction depicted in Table 1, entry 3, for
an extended time period (18 h) gave an improvement of the
kinetic 1.5:1 ratio of (E/Z)-11C (70% isolated yield, Table
1) to exclusively E-isomer. However, inspection of the crude
1H NMR spectrum revealed that an additional product had
formed with unique vinylic resonances at δ 6.38 (dd, J )
15, 11 Hz, 1H), 6.13 (d, J )11 Hz, 1H), and 5.71 (dt, J )
15, 7 Hz, 1H) ppm, consistent with a terminally substituted
diene substructure (Scheme 3). On the basis of these data,
Scheme 3. Trapping of Isomerization Intermediate
The rapid reactions led us to investigate the magnitude of
the accelerated reaction rate compared to that of simple
alkenes.11 We conducted a competition experiment using
propargyl benzoate 6a and 1 equiv each of 1-hexene and
allyl alcohol 7. After heating for 20 min at 55 °C, the reaction
was quenched with 5 and the crude product ratio was
determined by 1H NMR analysis against an internal standard
(mesitylene). We found 40% (E)-diene derived from allyl
alcohol 7 and 17% (E)-diene from 1-hexene. Under these
conditions, this experiment shows that there is a ca. 2.3-
fold rate enhancement by free hydroxyl functionality in enyne
metathesis.12 This is in accord with Hoye and Zhao’s findings
in the ring-closing alkene metathesis using the first generation
Grubbs carbene. The finding also strongly suggests an
alkylidene first mechanism with this 1-alkyne. It is the first
indication that we know of that different substitution on the
alkene affects rate in the cross enyne metathesis. Alkene
reactivity forms the basis for the selectivity model advanced
by the Grubbs group for cross alkene metathesis.13
we gathered that a 1,5-hydride shift had occurred. Unfortu-
nately, this byproduct could not be separated from the diene
(E)-11C.
The products were separated after an in situ cycloaddition
of the (E)-diene. We reasoned that putative hydride shift
product 19 would exist in the s-trans conformation, making
it unreactive in the thermal cycloaddition. The thermal
cycloaddition with N-phenyl maleimide provided cycloadduct
20 in 36% yield along with recovered 19, obtained in 33%
yield. The major (E)-diene 11C underwent [4 + 2] cycload-
dition cleanly, whereas the isomeric product s-trans-19 was
recovered unchanged from the reaction. At this stage, the
products could be separated and their structures indepen-
dently established by spectroscopic techniques. Diene s-trans-
19 presumably came from the intermediate Z-isomer 11C
by a 1,5-hydride shift (eq 4), though it was unclear what
promoted this reactivity. Equilibrium presumably favors 19
due to greater alkyl substitution on the resulting 1,3-diene.
Longer reaction times affected the product distribution.
Though alkyne consumption was complete in less than an
hour, we investigated extended heating of the reaction in an
attempt to obtain higher E-selectivity. On the basis of earlier
work,14 it was expected that a secondary, E-selective
alkene-diene metathesis would upgrade the ratio of (E)-
(6) (a) Lynn, D. M.; Mohr, B.; Grubbs, R. H. J. Am. Chem. Soc. 1998,
120, 1627–1628. (b) Connon, S. J.; Blechert, S. Bioorg. Med. Chem. Lett.
2002, 12, 1873–1876. (c) Binder, J. B.; Blank, J. J.; Raines, R. T. Org.
Lett. 2007, 9, 4885–4888. (d) Gallivan, J. P.; Jordan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 2005, 46, 2577–2580. (e) Hong, S. H.; Grubbs, R.
H. J. Am. Chem. Soc. 2006, 128, 3508–3509. (f) Jordan, J. P.; Grubbs, R. H.
Angew. Chem., Int. Ed. 2007, 46, 5152–5155.
(7) Imahori, T.; Ojima, H.; Tateyama, H.; Mihara, Y.; Takahata, H.
Tetrahedron Lett. 2008, 49, 265–268.
(8) Stragies, R.; Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2518–2520.
(9) Galan, B. R.; Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister, J. B.;
Diver, S. T. Org. Lett. 2007, 9, 1203–1206.
(10) Complete consumption of the alkyne was observed.
(11) (a) For a rate study of enyne metathesis with 1-hexene: Galan, B. R.;
Giessert, A. J.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2005, 127,
5762–5763. (b) DFT calculations: Lippstreu, J. J.; Straub, B. F. J. Am. Chem.
Soc. 2005, 127, 7444–7457.
(4)
(12) Alkene homodimerization was not detected. The reaction was run
to partial alkyne conversion and gave clean conversion to the diene products
of enyne metathesis. Further rate studies are being pursued.
(13) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
The causative agent for the hydride shift was investigated
further. Control studies were carried out on the purified diene
(E/Z)-11C. When this E/Z mixture was purified away from
(14) Giessert, A. J.; Diver, S. T. J. Org. Chem. 2005, 70, 1046–1049.
Org. Lett., Vol. 10, No. 10, 2008
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the ruthenium catalyst and heated under the reaction condi-
tions (DCE, reflux, 18 h), no 1,5-hydride shift product was
observed, and the E/Z mixture was recovered unchanged.
This ruled out a simple thermal isomerization and suggested
that a ruthenium-derived species was causing isomerization.
We considered that the longer heating periods decomposed
the Grubbs carbene into ruthenium hydrides. If this occurred,
then the 1,5-hydride shift would have been caused by
ruthenium hydrides.
(2:1 E/Z, Table 2, entry 1) was irradiated in the presence of
10 mol % of I2 to give 99% yield of (E)-13A. This procedure
is simple and very effective for converting an E/Z mixture
to the pure E-isomer.
(5)
Ruthenium hydrides15 formed in situ caused 1,5-hydride
shift in crude reaction mixtures of 11C. We conducted
metathesis as defined in entry 3, Table 1, to obtain an E/Z
mixture of 11C. To this crude mixture was added 50 mol %
of NaBH4 using Schmidt’s procedure15c to form ruthenium
hydrides in situ from the Grubbs catalyst 1. After 2 h of
heating at 60 °C in 1,2-DCE, only (E)-11C and 1,5-hydride
The presence of the hydroxyl group near the diene permits
directable, chemoselective transformation. Diene (E-)13A
was epoxidized under catalytic Sharpless asymmetric condi-
tions to give 21 in 58% isolated yield (eq 5). We foresee
additional substrate-directable transformations18 utilizing the
hydroxyl group, conveniently introduced through catalytic
enyne metathesis.
In conclusion, we have demonstrated that free hydroxylic
functionality is permitted in the alkenes used in cross enyne
metathesis. The alcohol provides a rate enhancement com-
pared to that of simple hydrocarbon alkenes. We observed a
1,5-hydride shift in the minor (Z)-diene which could be
minimized under short reaction times. We also used a simple
(nonmetathesis) procedure for the isomerization of an E/Z
mixture into (E)-diene. Last, the hydroxyl group provides a
handle to direct a chemoselective epoxidation of the diene
moiety. Further diene functionalization methods and detailed
kinetic studies of unsaturated alcohol-alkyne metathesis will
be reported in due course.
1
shift product 19 were observed in the crude H NMR. This
experiment illustrates that ruthenium hydrides are competent
to produce the isomerization by hydride shift under typical
reaction conditions.
The hydride shift did not pose a general problem in this
study due to the typically short reaction times (ca. 30-40
min) using a large excess of 1,ω-alkenol. Under these
conditions, the enyne metathesis is so fast that longer periods
of heating are not necessary. The long periods of heating in
the presence of the large excesses of alcohol are likely to
account for decomposition of the metal carbenes.5a,16 At short
reaction times, this is not problematic for the enyne metath-
esis.
Conversion of an E/Z isomeric mixture to the E-isomer
was accomplished through application of a classical isomer-
ization method using catalytic I2, hν (eq 5).17 To the best of
our knowledge, this equilibration has not been used to
upgrade E/Z ratio from E/Z mixtures produced through
nonstereoselective cross metathesis. A major shortcoming
of metathesis is the low stereoselectivity, and there are few
ways of dealing with this problem. The crude mixture 13A
Acknowledgment. This work was partially supported by
the Petroleum Research Fund (PRF AC-44202) and the NSF
(CHE-601206). J.R.C. acknowledges the NSF-REU program
at SUNY Buffalo (CHE-453206) for summer support. The
authors thank Dr. Amol Kulkarni (U. Pitt.) for some
preliminary observations, and we thank Materia (Pasadena,
CA) for supplying Grubbs’ catalyst.
(15) For leading references on the isomerization by ruthenium hydrides
under nominal metathesis conditions, see: (a) Sutton, A. E.; Seigal, B. A.;
Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390–
13391. (b) Schmidt, B. Eur. J. Org. Chem. 2003, 816–819. (c) Schmidt, B.
J. Org. Chem. 2004, 69, 7672–7687. (d) Schmidt, B.; Biernat, A. Org. Lett.
2008, 10, 105–108.
Supporting Information Available: Experimental pro-
cedures and full characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Dinger, M. B.; Mol, J. C. Organometallics 2003, 22, 1089–
1095. (b) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am.
OL800523J
Chem. Soc. 2003, 125, 10103–10109
.
(17) Use of catalyst I2/hν for diene isomerization: Van Rossum, A. J. G.;
De Bruin, A. H. M.; Nivard, R. J. F. J. Chem. Soc., Perkin Trans. 2 1975,
1036–1042.
(18) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307–1370.
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