Cycloheptadiene Ring Synthesis by Tandem Intermolecular Enyne Metathesis

Article abstract of DOI:10.1021/ol035246y

(Equation presented) The tandem intermolecular enyne metathesis between 1-alkynes and cyclopentene is reported, providing 2-substituted 1,3-cycloheptadienes. The success of the intermolecular reaction hinges on an appropriate balance between cycloalkene r

Full text of DOI:10.1021/ol035246y

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3463-3466
Cycloheptadiene Ring Synthesis by
Tandem Intermolecular Enyne
Metathesis
Amol A. Kulkarni 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 5, 2003
ABSTRACT
The tandem intermolecular enyne metathesis between 1-alkynes and cyclopentene is reported, providing 2-substituted 1,3-cycloheptadienes.
The success of the intermolecular reaction hinges on an appropriate balance between cycloalkene ring strain and reactivity of the alkyne.
Tandem reactions permit the rapid assembly of molecular
complexity, ideally through simple carbon-carbon bond-
forming reactions. Alkene and enyne metathesis offer a
convenient and catalytic means for constructing carbon-
carbon bonds.1 Recently, we reported a tandem metathesis
for the construction of 1,3-cyclohexadienes from acyclic
precursors, 1-alkynes and 1,5-hexadiene.2 Such reactions
capitalize on a consecutive, in situ ring-closing metathesis
that produces the desired ring. In this Communication, we
report an atom-economical synthesis of 1,3-cycloheptadienes
through intermolecular enyne metathesis of cyclopentene and
1-alkynes (Scheme 1).
Scheme 1. Cyclopentene-Alkyne Metathesis
It was anticipated from early work with tungsten Fischer
carbene catalysts that the reactants of eq 1 would give
metathesis polymerization, and the desired ring synthesis was
expected to be difficult. Depending on ring strain of the
cycloalkene, ring-opening alkene metathesis polymerization
(ROMP) should be favorable.3 Katz discovered enyne
metathesis while studying the influence of alkyne modifiers
on cycloalkene polymerization, using the aforementioned
tungsten Fischer carbene complexes.4 Katz found that small
quantities of alkynes resulted in polymers of increased mean
length. For the tandem metathesis of eq 1 to be successful,
(1) Alkene metathesis reviews: (a) Grubbs, R. H.; Miller, S. J.; Fu, G.
C. Acc. Chem. Res. 1995, 28, 446-452. (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450. (c) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043. (d) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. Enyne metathesis reviews: (e) Mori, M. Top.
Organomet. Chem. 1998, 1, 133-154. (f) Poulsen, C. S.; Madsen, R.
Synthesis 2003, 1-18.
(3) Ivin, K. J., Mol, I. C., Eds. Olefin Metathesis and Metathesis
Polymerization, 2nd ed. Academic Press: New York, 1996. (b) Ivin, K. J.
Cycloalkenes and Bicycloalkenes. In Ring-Opening Polymerization; Ivin,
K. J., Saegusa, T., Eds.; Elsevier: London, 1984, Chapter 3.
(4) (a) Katz, T. J.; Lee, S. J.; Nair, M.; Savage, E. B. J. Am. Chem. Soc.
1980, 102, 7940-7942. (b) Katz, T. J.; Sivavec, T. M. J. Am. Chem. Soc.
1985, 107, 737-738.
(2) Smulik, J. A.; Diver, S. T. Tetrahedron Lett. 2001, 42, 171-174.
10.1021/ol035246y CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/26/2003

the polymeric pathway must be overcome by alkyne-alkene
metathesis. We were interested in learning what substrate
parameters would be able to meet these criteria.
Table 1. Optimization Studies
Intramolecular, tandem reactions of dienes and alkynes
have been used for ring synthesis. In all of the related
literature examples, the alkyne and alkene are contained in
the same molecule. The Grubbs group demonstrated the
utility of tandem enyne metathesis with dienynes, where ring-
closing enyne metathesis and another ring-closing alkene
metathesis were used to generate bicyclic dienes.5 Blechert
has reported domino metathesis, which results in cyclore-
arrangement. This process involves cyclopentene ring-
opening metathesis followed by ring-closing enyne metath-
esis.6 Tandem ring-opening/ring-closing enyne metathesis of
N-propargyl allyl amides was reported by Mori and Kita-
mura.7 It was found that ethylene was needed to suppress
ring-opening polymerization, competitive with the intramo-
lecular process. Seven-membered rings and larger were
produced in the intramolecular cascade metathesis of Mori
and co-workers.7b Recently, Banti and North described a ring-
opening/double-ring-closing enyne metathesis.8 Outside of
the mechanistic superfamily of carbene-mediated enyne
metathesis, it should be noted that the intramolecular reaction
of cycloalkenes with alkynes is known from work by Trost
using Pd(II)- and Pt(II)-catalyzed enyne bond reorganization.9
Ru cat.
yield
(%)a
entry
alkyne
(in mol %)
temperature
1
2
3
4
5
6
7
8
9
5A
5A
5A
5A
5A
5B
5B
5B
5B
5B
5B
5B
1 (5 mol %)
1 (5 mol %)
2 (5 mol %)
3 (5 mol %)
4 (5 mol %)
1 (5 mol %)
2 (5 mol %)
3 (5 mol %)
4 (5 mol %)
1 (5 mol %)
2 (5 mol %)
3 (5 mol %)
110 °C (sealed tube)
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
22
48
45
42
b
56
48
55
b
10
11
12
reflux
room temp
room temp
17
40
38
a Isolated yield, 0.2 mmol scale. b No product formed in these rats.
through syringe pump addition.10 Over 12 h addition times,
polymer was still present but significantly reduced. Use of
fewer equivalents of cyclopentene resulted in incomplete
consumption of alkyne, partly due to evaporative loss of
cyclopentene.
The intermolecular reaction between cycloalkenes and
alkynes is potentially more difficult for several reasons.
Foremost, the intermolecular reaction will be more prone to
polymerization since alkene ring-opening produces an alky-
lidene that is not suspended near an alkyne, making alkene
homopolymerization (via ROMP) a likely outcome. Second,
an intermolecular reaction does not have geometric ring
constraint to enforce stereochemistry of the newly formed
alkene, and so the newly formed alkene is produced as a
mixture of (E)- and (Z)-isomers. This is a current problem
for intermolecular enyne metathesis.
A variety of ruthenium-carbene complexes initiated the
cross enyne metathesis. The Hoveyda catalyst 211 initiates
the reaction with results comparable to those of the second-
generation Grubbs’ catalyst 1 (entries 3, 7). Grubbs’ pyridine
solvate 312 effectively catalyzed the desired transformation
(entries 4, 8) but gave lower conversions and yields when
conducted at room temperature (entry 12). Since these are
very fast initiators for alkene metathesis, we suggest that
the refluxing temperature more efficiently converts the
intermediate vinylcarbenes to diene products. The first-
generation catalyst did not catalyze the cycloheptadiene
synthesis (entries 5, 9). From earlier work,2 we expected the
formation of geometrical isomers in a ca. 1:1 ratio. Surpris-
ingly, one major product was obtained.
The scope of the cyclopentene-alkyne cross metathesis
is illustrated in Table 2. The reactions were conducted under
standard high dilution conditions (syringe pump addition over
12-20 h). In all cases, the cycloheptadiene was obtained as
a single product, although trace dimer could be observed
(TLC) in isolated runs. The propargyl esters underwent
reaction in high yield (entries 1, 2), and propargylic substitu-
tion did not diminish the chemical yields (entries 3, 4). The
coordinating propargyl benzyl ether 11 and propargyl silyl
ether 13 gave good yields (entries 5, 6). Aromatic or aliphatic
groups could also be introduced onto the cycloheptadiene
ring by suitable choice of alkyne (entries 7, 8). The
Optimization of the cycloalkene-alkyne metathesis with
respect to catalyst and reaction conditions is summarized in
Table 1. Direct mixing of reactants and heating in a sealed
tube at 110 °C produced the 2-substituted 1,3-cyclohepta-
diene, albeit in low isolated yield (entry 1). Once the high
reaction temperatures were found to be unnecessary for
catalyst initiation and sustained catalysis, reactions were
carried out in refluxing dichloromethane with better results
(entry 2). The significant amount of baseline polymer
produced was suppressed by maintaining high dilution
(5) (a) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. 1994,
116, 10801-10802. (b) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.;
Grubbs, R. H. J. Org. Chem. 1996, 61, 1073-1081.
(6) (a) Ruckert, A.; Eisele, D.; Blechert, S. Tetrahedron Lett. 2001, 42,
5245-5247. (b) Randl, S.; Lucas, N.; Connon, S. J.; Blechert, S. AdV. Synth.
Catal. 2002, 344, 631-633.
(7) (a) Kitamura, T.; Mori, M. Org. Lett. 2001, 3, 1161-1163. (b) Mori,
M.; Kuzuba, Y.; Kitamura, T.; Sato, Y. Org. Lett. 2002, 4, 3855-3858.
(8) (a) Banti, D.; North, M. Tetrahedron Lett. 2002, 43, 1561-1564.
(b) Banti, D.; North, M. AdV. Synth. Catal. 2002, 344, 694-704.
(9) (a) Trost, B. M.; Trost, M. K. Tetrahedron Lett. 1991, 32, 3647-
3650. (b) Trost, B. M.; Trost, M. K. J. Am. Chem. Soc. 1991, 113, 1850-
1852. (c) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801-
3810.
(10) Snapper used syringe pump addition to suppress ROMP in order to
achieve selective cross alkene metathesis; see: Randall, M. L.; Tallarico,
J. A.; Snapper, M. L. J. Am. Chem. Soc. 1995, 117, 9610-9611.
3464
Org. Lett., Vol. 5, No. 19, 2003

Scheme 2. Bifurcation between ROMP and Enyne Metathesis
Table 2. Scope of Cyclopentene-Alkyne Metathesis
carbenes 27. The regiochemistry of this step cannot be
deduced from product 28. The Z-isomer (2Z)-27 can undergo
ring-closing metathesis with regeneration of the benzylidene
initiator (Scheme 2, panel b). Because the (E)-isomer (2E)-
27 cannot experience ring closure, it is likely to react with
cyclopentene, which is present in molar excess. However,
reaction with cyclopentene would give a new E,Z-mixture,
(5E,Z)-29. In this instance, the Z-isomer is geometrically-
poised for backbiting which would release more cyclohep-
tadiene. The E-isomer (5E)-29 reacts with cyclopentene to
give an oligomer, which explains the remaining mass balance
of alkyne.14
Previous examples of cross enyne metathesis have utilized
1-alkenes. With 1-alkenes, there is the possibility of generat-
ing a reactive methylidene, [Ru] ) CH2, which adds to the
alkyne with high regioselectivity.15a In the ring synthesis
reported here, it is not possible to produce a methylidene,
so the reaction must proceed through the intermediacy of
ruthenium alkylidenes.15 This mechanistic possibility has
been considered in certain ring-closing metatheses.15b,c To
the best of our knowledge, this is unprecedented for an
intermolecular enyne metathesis.
a Yield on 2.5 mmol scale. b Conversion by NMR.
homopropargylic series gave similar results (entries 9, 10)
as did the propargyl tosylamide substrate 23 (entry 11). Given
the expectation of a nonstereoselective cross metathesis, the
fact that yields exceeded 50% was unexpected. The removal
of the ruthenium byproducts was accomplished using DMSO
as prescribed by Georg.13
The ring synthesis appears to be confined to terminal
alkynes. With 1,4-diacetoxy-2-butyne, only alkene polymer
was observed without significant consumption of the alkyne.
Presumably, the internal alkyne reacts intrinsically slower
with alkylidene 25, thereby partitioning into the ROMP
pathway (25 to 26, Scheme 2, panel a).
A working hypothesis for the mechanism of the cross
metathesis is illustrated in Scheme 2. Presumably the reaction
is triggered by ring-opening of the cyclopentene. The alkyne
must be able to intercept dienylidene 25 before cycloalkene
complexation (Scheme 2, panel a), an additional step that is
possibly reversible. The high dilution helps suppress cy-
cloalkene homopolymerization. Addition of alkylidene 25
to the alkyne will produce two new stereoisomeric vinyl
(14) An extension of the proposed backbiting RCM depicted in Scheme
2, panel b, is that polymerization is unavoidably occurring, even at low
cyclopentene concentration. Polymeric alkylidene could then consume
alkyne to produce a polymeric vinylcarbene analogous to 27, which could
backbite to give the observed cycloheptadiene.
(15) (a) Stragies, R.; Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.
1997, 36, 2518-2520. For related mechanistic discussion, see: (b) Hoye,
T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1, 277-279. (c)
Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem., Int. Ed. 2001,
40, 4274-4277.
(11) (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.
(12) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew.
Chem., Int. Ed. 2002, 41, 4035-4037.
(13) Ahn, Y. M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411-
1413.
Org. Lett., Vol. 5, No. 19, 2003
3465

Scheme 3. Cycloaddition of 1,3-Cycloheptadienes with
Scheme 4. Synthesis of a Novel Silepin
Singlet Oxygen
In summary, a classic alkyne-promoted cycloalkene po-
lymerization reaction has been transformed into a useful
synthesis of seven-membered rings. Use of the second-
generation ruthenium carbenes and high dilution conditions
were critical to the ring synthesis. Notable features of the
reaction include its mildness and that the products are
obtained as single stereoisomers. The success of the inter-
molecular reaction is thought to be a result of a properly
balanced rate of enyne metathesis, which can outcompete
alkene (or alkyne-assisted) ring-opening metathesis polym-
erization. Extension of the reaction to other ring sizes and
to cycloalkenes bearing heteroatom substitution is under
active study in our group.
The diene products could be functionalized at the 1- and
4-positions. For example, 6A gave clean cycloaddition with
singlet oxygen to produce the endoperoxide 30. The peroxide
cycloadduct was reductively cleaved (Zn, HOAc) to afford
diol 31 (eq 4, Scheme 3). Similarly, regioselective base-
induced fragmentation of endoperoxide 30 gave a 27:1
mixture of regioisomeric γ-hydroxy cycloheptenones 32 and
33 (eq 5).
Guided by the crude approximation that intermediately
strained cycloalkenes will give the ring products based on
their proclivity toward ROMP16 (“ROMPability”), we in-
vestigated whether silole 34 would undergo the enyne
metathesis. Heating the silole and alkyne 7 in benzene
provided the novel silepin 35 (Scheme 4). This is remarkable
since molecular modeling (MMX) of the silepin reveals that
the diene is twisted out of conjugation (ca. 90°), suggesting
that this enyne metathesis derives less enthalpic driving force
than its unconstrained relatives.17 This single result demon-
strates that the ring synthesis is adaptable to other cycloalk-
enes and may have further utility to access heterocycles.
Acknowledgment. The authors thank Tony Giessert for
helpful discussions and Dr. Richard Fisher (Materia, Pasa-
dena, CA) for catalyst support. We gratefully acknowledge
the Kapoor Foundation for a graduate fellowship (to A.A.K.)
and the National Cancer Institute (R01CA090603) for
financial support of this work.
Supporting Information Available: Experimental pro-
cedures and full characterization data for new compounds
6, 8, 10, 12, 14, 17, 18, 20, 22, 24, 30, 31, 32, 35. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035246Y
(17) Atropisomers of 35 are enantiomers, but when a chiral center is
present, the dihedral twist gives rise to diastereomers as seen in the silepin
derived from alkyne 5B (data not shown).
(16) Ability of a cycloalkene to give ring-opening metathesis polymer-
ization suggests minimally that the cycloalkene will initiate.
3466
Org. Lett., Vol. 5, No. 19, 2003