Synthetic studies toward polytwistane hydrocarbon nanorods

Article abstract of DOI:10.1021/jo502618g

A synthetic strategy toward the intriguing hydrocarbon nanorod polytwistane is outlined. Our approach aims toward the polymerization of acetylene starting from precursors that would provide a helical bias for the formation of polytwistane. Both transition-metal-catalyzed and radical polymerizations were investigated. Two potential initiator molecules were synthesized that could be used for either approach. Although the intended regioselectivities were not observed, unusual organopalladium complexes and numerous compounds with novel carbon skeletons were obtained.

Full text of DOI:10.1021/jo502618g

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Featured Article
Synthetic Studies Toward Polytwistane Hydrocarbon Nanorods
Martin Olbrich, Peter Mayer, and Dirk Trauner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502618g • Publication Date (Web): 16 Dec 2014
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Synthetic Studies Toward Polytwistane Hydrocarbon Nanorods
Martin Olbrich, Peter Mayer and Dirk Trauner*
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Department of Chemistry and Pharmacy, Ludwig-Maximilians-Universität München, and Munich
Center for Integrated Protein Science, Butenandtstr. 5–13, 81377 Munich, Germany
Corresponding Author E-mail: dirk.trauner@cup.uni-muenchen.de
Abstract
A synthetic strategy toward the intriguing hydrocarbon nanorod polytwistane is outlined. Our
approach aims toward the polymerization of acetylene starting from precursors that would
provide a helical bias for the formation of polytwistane. Both transition metal catalyzed and
radical polymerizations were investigated. Two potential initiator molecules were synthesized
that could be used for either approach. Although the intended regioselectivities were not
observed, unusual organopalladium complexes and numerous compounds with novel carbon
skeletons were obtained.
Introduction
Carbon nanotubes (CNT) feature a variety of attractive mechanical, thermal and electrical
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properties. This has led to their use in lightweight composite materials and medical devices
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and makes them interesting for a range of future applications. The physical properties of
CNTs are highly dependent on their geometrical makeup, which is determined by the
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combination of tube diameter and structural type (armchair vs. zig-zag vs. chiral). These
parameters are described commonly by the vectorial indeces (n,m) which indicate how a sheet
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of graphene would have to be wrapped up to form the corresponding CNT.
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Considering the relationship of graphene with graphane, it is interesting to speculate about
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the relationship of the smallest CNTs with their fully hydrogenated counterparts. As shown
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in Figure 1, armchair (2,2)-CNT (1) corresponds to hydrocarbon nanorod 4, which was first
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proposed by Stojkovic et al.. Similarly, zig-zag (3,0)-CNT 2 corresponds to hydrocarbon
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nanorod 5. The smallest possible chiral carbon nanotube, viz. chiral (2,1)-CNT 3, is related to
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the recently proposed hydrocarbon nanorod polytwistane (6) in the same way. Each of these
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hydrocarbon nanorods consists of cyclohexane rings locked in distinct conformations. For
example in hydrocarbon 4 all of the rings reside in the boat conformation, whereas in nanorod
5 both boat and chair conformations are present. Polytwistane (6) exhibits only D -symmetric
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twist-boat cyclohexanes, thus retaining helical chirality. All of these polymeric structures are
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isomers of polyacetylene (C H ) and display hydrogen atoms and sp hybridized carbon
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atoms that possess the same chemical environment.
Figure 1. Very small CNTs and their completely hydrogenated equivalents.
One way to access nanorods 4-6 would be to completely hydrogenate the corresponding
CNTs 1-3. This has, in fact, been recently studied in order to use CNTs as a material for
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hydrogen storage. Although these investigations yielded partially hydrogenated CNTs, the
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products could not be fully characterized.
Several strategies could be imagined to rationally synthesize polytwistane (6). The first
strategy relies on the polymerization of benzene via Diels-Alder reactions to form laticyclic
conjugated polyenes (Scheme 1). These could then be converted to polytwistane (6) via
N-type cyclizations. A similar pathway was also formulated by Badding and co-workers for
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the formation of a sp hybridized hydrocarbon nanorod from benzene at very high pressures
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(20 GPa).
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Scheme 1. Proposed synthesis of polytwistane (6) via a Diels-Alder polymerization / N-type
cyclization strategy.
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The second approach starts with the polymerization of acetylene to yield the well-known sp
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hybridized polyacetylene (Scheme 2). This material could then be transformed into
polytwistane (6) via a two-stage radical olefin polymerization. Indeed, a case of acetylene
polymerization has been reported in the literature where partially saturated species were
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observed.
Scheme 2. Proposed synthesis of polytwistane (6) by a radical polymerization of
polyacetylene.
The third, and more rational strategy for the synthesis of polytwistane relies on the
polymerization of acetylene from an initiator INR that carries an alkenyl halide functionality
(X = Br, I) (Scheme 3). We envisioned that both transition metal catalyzed and radical
polymerization of acetylene could afford polytwistane (6). In the case of a transition metal
catalyzed process, the first step would be an oxidative insertion into the alkenyl halide bond,
thereby generating an alkenyl transition metal complex. In a subsequent intramolecular
carbometallation step, a new six-membered ring would be formed (a). This step is crucial for
the outcome of the polymerization as two possible cyclization modes exist. Due to the
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bicyclic structure of the initiator compound, the desired 6-endo-trig cyclization has to
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compete with the undesired 5-exo-trig cyclization. In the next step an intermolecular
carbometallation of an alkyne would occur (b). Alternation of intra- and intermolecular
carbometallation steps of alkenes and acetylene, respectively, would then lead to polytwistane
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(6). In the case of a radical polymerization, the alkenyl halide would be cleaved homolytically
and the polymerization would proceed by alternating radical cyclizations (a) and radical
additions to acetylene (b).
Scheme 3. Proposed acetylene polymerization to polytwistane (6). a: intramolecular
cyclization. b: intermolecular addition. X = Br, I. Y = metal, radical.
Herein we describe the syntheses of a bicyclic and a tricyclic initiator molecule corresponding
to INR. Attempts to achieve both transition metal catalyzed and radical cyclizations are
discussed.
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Results and Discussion
Synthesis and Cyclization Attempts of Haloalkenylbicyclo[2.2.2]octene
In order to test the feasibility of the proposed polymerization process, the crucial cyclization
step was investigated first. For this purpose, the simple initiator molecules 9 and 10 were
synthesized (Scheme 4). Addition of acrolein to cyclohexa-1,3-diene (7) afforded known
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bicyclo[2.2.2]octenecarbaldehyde 8, which was converted to (Z)-alkenyl bromide 9 or
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(Z)-alkenyl iodide 10 using Stork-Zhao reactions.
Scheme 4. Synthesis of bicyclic initiator molecules 9 (X = Br) and 10 (X = I).
With 9 and 10 in hand, the stage was set for the exploration of the first cyclization via
oxidative addition to a transition metal followed by migratory insertion. To allow for
unambiguous characterization of the cyclization product, the reaction was first carried out
using stoichiometric amounts of Pd(PPh ) (Scheme 5). This resulted in the isolation of
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5-exo-trig cyclization products 11 and 12, the structures of which were confirmed by single
crystal X-ray diffraction. This finding is consistent with the major mode of cyclization
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reported for similar substrates. In an attempt to change the selectivity of the reversible
cyclization by adjusting the electronics, the neutral palladium complex 11 was converted to
cationic palladium complex 13 by treatment with AgBF and PPh . However, upon heating of
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species 13 no conversion to the desired twistenylpalladium complex 14 was observed.
Efforts to change the selectivity by using catalytic conditions with different palladium species
and a variety of hydride sources only gave double cyclization product 15, 5-exo-trig
cyclization product 16 and direct reduction product 17. The same was true for the radical
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cyclization of 9, which has been previously described in the literature.
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Scheme 5. Exploration of the cyclization step on bicyclic precursors 9 and 10.
A possible way to influence the steric and electronic parameters of the cyclization reaction
could be the introduction of methyl substituents. Therefore, two monomethyl- and one
dimethyl substituted bicyclic cyclization precursors (18, 19 and 20) were synthesized. The
synthesis was carried out analogously to the preparation of 9 and 10 (see Supporting
Information). Attempts to cyclize 18 using transition metal catalysis afforded only the
undesired 5-exo-trig cyclized product 21, along with the product of direct reduction 22
(Scheme 6). In the case of compound 19 these conditions yielded diene 23. The same result
was also observed in the reaction of alkenyl bromide 20. Stoichiometric palladation of 19
gave complex 25, which was characterized by single crystal X-ray diffraction (Scheme 7). By
contrast, in the reaction of its isomer 18 with a stoichiometric amount of Pd(0) the formation
of alkenylpalladium complex 26 was observed. This compound is one of the few
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alkenylpalladium complexes characterized by X-ray crystallography. In no case was the
desired 6-endo-trig product found.
Alkenyl halides 18, 19 and 20 were submitted to radical cyclization conditions as well. As in
the case of transition metal catalysis we observed the formation of 21, 22, 23 and 24,
respectively but could not identify any twistene structures.
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Scheme 6. Exploration of the cyclization step on bicyclic precursors 18, 19 and 20.
Scheme 7. Stoichiometric palladation of alkenyl bromides 18 and 19.
Given the reluctance of bicyclo[2.2.2]octenes 9 and 10 to undergo the desired cyclizations, we
decided to investigate precursors that contain a twist-boat motif, i.e. twistenes 27 and 28
(Scheme 8). We reasoned that this modification would provide a helical bias toward the
desired 6-endo-trig cyclization mode.
Scheme 8. Expansion of the precursor scaffold to helically bias the system.
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Synthesis and Cyclization Attempts of Haloalkenyltricyclo[4.4.0.0 ]decene
The next objective was to synthesize an initiator compound that incorporates the twistane
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skeleton. The synthesis of tricyclic compounds 27 and 28 started with the known
iodolactone 29 which was obtained in six steps from 1,3-cyclohexadiene (7), repeating the
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first steps of Whitlock’s twistane synthesis (Scheme 9). Reduction of 29 to diol 30, followed
by Swern oxidation, gave ketoaldehyde 31. Crude 31 could then be directly transformed to
ketoalcohol 32 in an aldol reaction yielding a separable 2 : 3 mixture of product and starting
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material, which could be recycled. Unfortunately, elimination of the secondary alcohol
could not be accomplished with standard reagents - such as Martin’s sulfurane, MsCl /
pyridine and Burgess reagent. An X-ray crystal structure of mesylate 33 established the
relative configuration of alcohol 32.
Scheme 9. Formation of the twistane core by an aldol reaction.
Conversion of 32 to xanthate 34 followed by a subsequent Chugaev elimination was then
investigated. However under the forcing conditions necessary, a retro-Diels-Alder reaction
followed by aromatization took place to afford phenol 36 as the major product (Scheme 10).
Scheme 10. Attempt to introduce the double bond by a Chugaev elimination.
Since elimination reactions were not viable, we decided to introduce the double bond via a
ketone. Oxidation of 32 gave diketone 37 which could be selectively converted into enol
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triflate 38 (Scheme 11). Palladium catalyzed reduction then gave the desired twistenone 35.
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A three step homologation of 35, via 39 and 40, then afforded twistenylcarbaldehyde 41 as a 3
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1 mixture of diastereomers in favor of the desired isomer shown. The diastereomers could
be separated by column chromatography and the configuration of the desired product was
confirmed by single crystal X-ray diffraction after conversion to the corresponding
dinitrophenylhydrazone (see SI). As in the synthesis of the bicyclo[2.2.2]octene systems the
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alkenyl halide handle was established using Stork-Zhao reactions to afford 27 and 28.
Scheme 11. Synthesis of haloalkenyltwistenes 27 and 28 from aldol product 32.
With haloalkenyltwistenes 27 and 28 in hand the crucial cyclization step could be investigated
again. The first cyclization attempt was carried out using stoichiometric amounts of
Pd(PPh ) , in order to facilitate the easy identification of the regiochemistry resulting from the
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cyclization. Indeed, from the reaction of bromoalkenyltwistene 27 with the Pd(0)-source
crystals could be obtained which were suitable for single crystal X-ray diffraction.
Disappointingly, the analysis of the X-ray structure showed that the undesired 5-exo-trig
cyclization mode was operational to yield isoditwistene palladium complex 42 (Scheme 12).
From the analogous reaction with iodoalkenyltwistene 28 only crystals of PdI (PPh ) were
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obtained. Attempts to thermally isomerize 42 to the desired 43 proved unsuccessful, resulting
in decomposition.
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Scheme 12. Palladium mediated cyclization of bromoalkenyltwistene 27.
Figure 2. ORTEP plots of the X-ray crystal structure of isoditwistenepalladium bromide 42.
Ellipsoids are scaled to 50% probability except for hydrogens which are of arbitrary size.
Phenyl rings are omitted for clarity. Color code: gray = C; black = H; red = Br, navy = Pd;
orange = P.
Next, we tested the cyclization using reductive transition metal catalyzed conditions
(Scheme 13). All conditions used only gave cyclopropane 44, a new hydrocarbon, as the only
identifiable product, but failed to deliver the desired ditwistene 45.
Scheme 13. Cyclization of haloalkenyltwistene 28 to cyclopropane 44 under reductive
transition metal catalyzed conditions.
It is well known that palladium mediated cyclizations occur predominantly following the exo
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mode for small to medium sized rings. It has been argued that reported cases of endo
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cyclizations in such systems actually take place in a sequence of two exo cyclizations
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followed by a rearrangement and this has been proven for several substrates.
From three
dimensional models it is obvious that this sequence of reactions is not possible for the present
system because of its high rigidity. After 5-exo-trig and 3-exo-trig cyclizations via 46 and 47
cyclopropane Pd-complex 48 would be formed (Scheme 14). The inversion of compound 48
to 49 cannot take place. Therefore, the ensuing rearrangement to ditwistene 50 is not possible
and cyclopropane 48 is converted to the corresponding palladium hydride and undergoes
reductive elimination as observed in the catalytic reactions.
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Scheme 14. Mechanism for the formation of cyclopropane 45.
In parallel to palladium catalysis, the cyclization was investigated employing reductive radical
conditions. Again we only obtained cyclopropane 44, whilst never observing ditwistene 45
(Scheme 15). Special attention was paid to the concentration of the reaction mixture, as the
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establishment of the thermodynamic equilibrium, no formation of the desired product 45
could be observed.
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Scheme 15. Cyclization of haloalkenyltwistene 29 to cyclopropane 45 under reductive
transition metal catalyzed conditions.
In radical chemistry, 5-exo-trig cyclizations occur very fast compared to 6-endo-trig
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cyclizations.
However, in cyclizations involving vinylradicals the product of 5-exo-trig
cyclization can interconvert to the product of the 6-endo-trig cyclization via a
cyclopropylcarbinyl radical. Unfortunately, the cyclopropylcarbinyl radical is the only species
that is trapped by the tin hydride in our case.
Further attempts to change the cyclization selectivity using among others carbolithiation
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conditions, atom-transfer-radical-cyclization (Cu , Bu Sn
AIBN ) conditions and
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irradiation with different light sources yielded none of the desired product. In an attempt to
exploit the thermodynamics in a series of cyclization reactions, the initiator molecules were
also submitted to polymerization conditions using an excess of an acetylene derivative.
Neither thermal nor photochemical conditions afforded polymeric materials.
Our investigations have led us to conclude that a “rational” approach to synthesizing
polytwistane (6) from acetylene, as outlined in Scheme 3, is challenging. This does not
preclude however, that polytwistane (6) could be synthesized from acetylene under high
temperature and / or high pressure conditions. It is also conceivable that fully saturated
polytwistane (6) could be made from the conducting polymer polyacetylene in its various
3
5
forms (Scheme 2). Investigations in this direction, as well as attempts to favor a radical
polymerization pathway by using substituted alkynes are currently underway in our
laboratories and will be reported in due course. Finally it should be noted that the
hydrocarbon nanorods recently obtained by the Badding group via ultra-high pressure
polymerization of benzene may well contain polytwistane (6) or polytwistane
10,13
substructures.
Conclusion
A synthetic route toward polytwistane via an initiator biased acetylene polymerization was
explored. Two initiator molecules with different helicity were synthesized. The simpler one
exhibits a bicyclo[2.2.2]octene unit wherein a cyclohexane is locked in the boat conformation.
In the second initiator molecule, cyclohexane rings are incorporated in the twist-boat
conformation. The critical first cyclization step of the proposed polymerization was studied
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on both systems. The regioselectivity of the Pd-mediated cyclization was elucidated
unambiguously by several X-ray analyses of the isolated novel Pd-complexes However, the
products were found to be exclusively formed by the undesired 5-exo cyclization mode. All
efforts to change the selectivity using reductive transition metal catalysis and reductive radical
conditions led only to undesired products but provided the X-ray crystal structure of a new
alkenylpalladium complex. In addition a structurally attractive new hydrocarbon has been
synthesized (compound 44).
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Experimental Section
General considerations. All reactions, unless stated otherwise, were carried out under a
positive pressure of N in flame-dried glassware. Commercial reagents and solvents were
2
used as purchased with the following exceptions. Tetrahydrofuran (THF) and diethylether
0
1
2
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(
Et O) were pre-dried over CaCl and distilled over sodium and benzophenone under a
2
2
nitrogen atmosphere immediately before use. Dichloromethane (CH Cl ), Et O, ethyl acetate
2
2
2
(EtOAc), hexanes and n-pentane for flash chromatography and workup were obtained from
technical grade by distilling in vacuo prior to use. Hexanes refers to the fraction of petroleum
that boils between 40 °C and 60 °C. All reactions were magnetically stirred and monitored by
analytical thin-layer chromatography (TLC) using silica gel 60 F254 glass-backed plates. Spots
were visualized under UV light (254 nm) or by application of aqueous stains of basic
potassium permanganate, ceric ammonium molybdate, anisaldehyde, dinitrophenylhydrazine
or vanillin followed by heating with a heat gun. The statement of drying a combined organic
layer includes the removal of the drying agent by filtration and washing of the residue with an
appropriate solvent. Flash column chromatography was performed on silica gel 60 (0.040–
0.063 mm). Yields refer to chromatographically and spectroscopically pure material.
Solutions were concentrated at 30 °C, if not specified otherwise. Nuclear magnetic resonance
(NMR) spectra were recorded in CDCl , DMSO-d or C D at 300 MHz, 400 MHz and
3 6 6 6
6
00 MHz for protons (75 MHz, 100 MHz and 150 MHz for carbons). For the measurement of
1
3
1
all C NMR spectra broadband H decoupling was employed. Chemical shifts (δ) were
calibrated using the residual undeuterated solvent as an internal reference and are according to
the common convention reported in parts per million (ppm) downfield relative to
tetramethylsilane (TMS). The chemical shifts of the reference solvents were defined
3
6
1
concurrent with the data from Nudelman and coworkers for CDCl : 7.26 ppm ( H NMR)
3
1
3
1
13
and 77.16 ppm ( C NMR), for DMSO-d : 2.50 ppm ( H NMR) and 39.52 ppm ( C NMR)
6
1
13
and for C D : 7.16 ppm ( H NMR) and 128.06 ppm ( C NMR). For the designation of
6
6
multiplicities the following abbreviations were used: s (singlet), d (doublet), t (triplet), br
broad) and m (multiplet) or combinations thereof. Protons and carbons were assigned using
2D spectra (HSQC, COSY, NOESY, HMBC). Infrared (IR) spectra were recorded on an
(
–
1
–
instrument with a Diamond ATR sensor for detection in the range from 4500 cm to 600 cm
1
.
Samples were prepared as a film for liquid or neat for solid substances. Data in the
–1
experimental part are given in units of cm . High resolution (HRMS) and low resolution
(
LRMS) mass spectra were recorded using electron ionization (EI) with a sector field mass
spectrometer or electrospray ionization (ESI) with a Fourier transform ion cyclotron
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resonance mass spectrometer. In the experimental part only the high resolution mass peak is
given and the used mode of ionization is stated. A graphical overview for the synthesis of
methyl substituted precursors 18, 19 and 20 and iodolactone 30 is enclosed in the Supporting
Information.
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Bicyclo[2.2.2]oct-5-ene-2-endo-carbaldehyde (8). To a solution of cyclohexadiene 7
(
7.00 mL, 6.01 g, 75.0 mmol, 1.00 eq.) in 2-methoxyethyl ether (75.0 mL) at room
temperature was added successively acrolein (25.0 mL, 21.0 g, 375 mmol, 5.00 eq.) and
BF ·OEt (1.39 mL, 1.60 g, 11.3 mmol, 0.150 eq.). The reaction mixture was stirred at room
3
2
temperature for 20 h. The mixture was diluted with H O (90 mL) and the aqueous layer was
2
extracted with Et O (3 x 90 mL). The combined organic layer was washed with H O (3 x
2
2
90 mL), dried (Na SO ) and concentrated in vacuo. Purification of the residue by flash
2
4
column chromatography (silica, n-pentane : Et O = 95 : 5) afforded bicycloaldehyde 8
2
(5.68 g, 56%) as a colorless oil.
1
R = 0.59 (n-pentane : Et O = 95 : 5); H NMR (300 MHz, CDCl ): δ = 9.43 (d, J = 1.6 Hz,
f
2
3
1
H), 6.31 (ddd, J = 8.0, 6.6, 1.2 Hz, 1H), 6.09 (ddd, J = 8.0, 6.4 , 1.2 Hz, 1H), 2.98 – 2.89 (m,
1H), 2.68 – 2.59 (m, 1H), 2.59 – 2.50 (m, 1H), 1.77 – 1.47 (m, 4H), 1.40 – 1.19 (m, 2H) ppm;
1
3
C NMR (75 MHz, CDCl ): δ = 204.3, 136.4, 131.0, 51.2, 31.0, 29.5, 27.0, 25.5, 25.1 ppm;
3
–1
IR (ATR): ṽmax = 2940, 2867, 1721, 1373, 1175, 1159, 1068, 952, 922, 850, 816, 700 cm ;
+
+
HRMS (EI): m/z for C H O [M] : calcd.: 136.0883, found: 136.0886.
9
12
5-(endo-(Z)-2-Bromoalkenyl)bicyclo[2.2.2]oct-2-ene
(9).
bromomethyl)triphenylphosphonium bromide (22.6 g, 51.8 mmol, 1.10 eq.) in THF
214 mL) was added KOt-Bu (5.81 g, 51.8 mmol, 1.10 eq.) at 78 °C. The resulting yellow
To
a
solution
of
(
(
reaction mixture was stirred at 78 °C for 15 min, after which time DMPU (26.7 mL, 28.4 g,
21 mmol, 4.70 eq.) and aldehyde 8 (6.41 g, 47.1 mmol, 1.00 eq.) were added successively.
2
The mixture was stirred for an additional 4 h at 78 °C, then diluted with hexanes (600 mL)
and filtered over celite. The residue was washed with hexanes (600 mL) and the combined
filtrates were concentrated in vacuo. Purification of the residue by flash column
chromatography (silica, hexanes : EtOAc = 100 : 1) afforded alkenyl bromide 9 (7.3 g, 73%)
as a colorless oil.
1
R = 0.69 (hexanes); H NMR (300 MHz, CDCl ): δ = 6.38 – 6.30 (m, 1H), 6.19 – 6.11 (m,
f
3
1H), 5.96 (dd, J = 6.9, 1.0 Hz, 1H), 5.81 (dd, J = 9.0, 6.9 Hz, 1H), 2.91 – 2.78 (m, 1H), 2.58 –
2
1
.51 (m, 1H), 2.51 – 2.44 (m, 1H), 1.93 (ddd, J = 12.5, 9.6, 2.6 Hz, 1H), 1.69– 1.57 (m, 1H),
13
.54 – 1.45 (m, 1H), 1.31 – 1.18 (m, 2H), 1.05 – 0.94 (m, 1H) ppm; C NMR (75 MHz,
CDCl ): δ = 141.7, 135.8, 132.1, 104.7, 38.8, 34.4, 33.8, 29.8, 25.9, 24.5 ppm; IR (ATR):
3
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ṽmax = 2936, 2864, 1616, 1374, 1323, 1290, 1277, 942, 913, 858, 805, 699, 670, 644, 627
–
1
+
+
cm ; HRMS (EI): m/z for C H Br [M] : calcd.: 212.0195, found: 212.0197.
1
0
13
5-(endo-(Z)-2-Iodoalkenyl)bicyclo[2.2.2]oct-2-ene
(10).
To
a
suspension
of
(iodomethyl)triphenylphosphonium iodide (4.67 g, 8.80 mmol, 1.10 eq.) in THF (35.0 mL) at
0
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8
9
0
0
°C was added a solution of KHMDS (1.00 M in THF, 8.80 mL, 8.80 mmol, 1.10 eq.). The
resulting yellow reaction mixture was stirred at 0 °C for 5 min, after which time the mixture
was cooled to 78 °C and DMPU (4.53 mL, 4.82 g, 37.6 mmol, 4.70 eq.) and a solution of
aldehyde 8 (1.09 g, 8.00 mmol, 1.00 eq.) in THF (24.0 mL) were added successively. The
mixture was stirred for 3 h at 78 °C and was then diluted with hexanes (110 mL) and filtered
over celite. The residue was washed with hexanes (330 mL) and the combined filtrates were
concentrated in vacuo. Purification of the residue by flash column chromatography (silica,
hexanes : EtOAc = 100 : 1) afforded alkenyl iodide 10 (1.21 g, 58%) as a colorless oil.
1
R = 0.87 (hexanes : EtOAc = 9 : 1); H NMR (300 MHz, CDCl ): δ = 6.37 – 6.30 (m, 1H),
f
3
6
.18 – 6.10 (m, 1H), 5.99 (dd, J = 7.2, 0.8 Hz, 1H), 5.87 (dd, J = 8.7, 7.2 Hz, 1H), 2.71 – 2.60
m, 1H), 2.60 – 2.51 (m, 1H), 2.51 – 2.43 (m, 1H), 1.94 (ddd, J = 12.4, 9.6 Hz, 2.7 Hz, 1H),
.70 – 1.57 (m, 1H), 1.57 – 1.46 (m, 1H), 1.35 – 1.16 (m, 2H), 1.00 (dddd, J = 12.4, 4.7,
(
1
1
3
2.9, 2.9 Hz, 1H) ppm; C NMR (75 MHz, CDCl ): δ = 148.0, 135.8, 132.2, 78.9, 43.7, 34.4,
3
3
3.5, 29.8, 25.9, 24.5 ppm; IR (ATR): ṽmax = 2935, 2863, 1604, 1319, 1268, 1238, 912, 857,
–1
+
+
8
01, 712, 699, 660, 636, 610 cm ; HRMS (EI): m/z for C H I [M] : calcd.: 260.0056,
10 13
found: 260.0064.
3
,7
Tricyclo[4.3.1.0 ]dec-4-ene-2-yltriphenylphosphinepalladium(II) bromide (11). To a
solution of Pd(PPh ) (497 mg, 0.430 mmol, 1.00 eq.) in benzene (3.00 mL) was added
3 4
Z-alkenyl bromide 9 (91.6 mg, 0.430 mmol, 1.00 eq.) by syringe. The yellow reaction mixture
was heated to 65 °C for 2 h. The mixture was allowed to cool to room temperature and Et O
2
(
50 mL) was added, precipitating a white solid. The precipitate was filtered off and the filtrate
was allowed to stand. Upon slow evaporation of the solvent the title palladium complex 11
122 mg, 49%) crystallized in the form of yellow platelets. Crystals suitable for single crystal
(
X-ray diffraction could be obtained from this mixture.
1
mp 148 °C (dec.); H NMR (600 MHz, CDCl ): δ = 7.74 – 7.68 (m, 6H), 7.44 – 7.36 (m,
3
9H,), 6.91 – 6.86 (m, 1H), 6.19 – 6.15 (m, 1H), 3.13 – 3.05 (m, 1H), 2.90 – 2.82 (m, 1H), 2.56
–
2.49 (m, 1H), 2.21 – 2.14 (m, 1H), 1.74 (dd, J = 13.0, 8.1 Hz, 1H), 1.60 – 1.49 (m, 2H),
1
3
1
.44 – 1.35 (m, 1H), 1.25 – 1.22 (m, 1H), 1.02 – 0.90 (m, 2H) ppm; C NMR (150 MHz,
CDCl ): δ = 134.6 (d, J = 12.3 Hz), 133.4 (d, J = 9.8 Hz), 131.2 (d, J = 43.8 Hz), 130.7 (d,
3
J = 2.4 Hz), 128.5 (d, J = 10.4 Hz), 87.0 (d, J = 13.0 Hz), 48.7 (s), 46.3 (s), 41.4 (d,
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J = 2.4 Hz), 33.1 (s), 31.9 (s), 30.1 (d, J = 5.1 Hz), 26.9 (d, J = 7.9 Hz), 18.1 (s) ppm;
–
1
IR (ATR): ṽmax = 2924, 2857, 1333, 977, 910, 808, 731, 701 cm ; HRMS (ESI+): m/z for
+
+
C H PPd [M–Br] : calcd.: 501.0958, found: 501.0962.
28
28
3
,7
Tricyclo[4.3.1.0 ]dec-4-ene-2-yltriphenylphosphinepalladium(II) iodide (12). To a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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solution of Pd(PPh ) (497 mg, 0.430 mmol, 1.00 eq.) in benzene (3.00 mL) was added
3
4
Z-alkenyl iodide 10 (112 mg, 0.430 mmol, 1.00 eq.). The yellow reaction mixture was heated
to 50 °C for 2 h. The mixture was allowed to cool to room temperature and Et O (25 mL) was
2
added, precipitating a white solid. The precipitate was filtered off and the filtrate was allowed
to stand. Upon slow evaporation of the solvent the title palladium complex 12 (150 mg, 56%)
crystallized in the form of yellow platelets. Crystals suitable for single crystal X-ray
diffraction could be obtained from this mixture.
1
R = 0.49 (hexanes : EtOAc = 3 : 1); mp 136 °C (dec.); H NMR (600 MHz, CDCl ): δ = 7.72
f
3
–
1
1
7.65 (m, 6H), 7.41 – 7.36 (m, 9H), 7.20 – 7.11 (m, 1H), 6.05 – 5.96 (m, 1H), 3.21 – 3.11 (m,
H), 2.87  2.82 (m, 1H), 2.56 – 2.49 (m, 1H), 2.25 – 2.18 (m, 1H), 1.71 (dd, J =
3.1, 8.1 Hz, 1H), 1.63 – 1.50 (m, 2H), 1.46 – 1.38 (m, 1H), 1.33 – 1.27 (m, 1H), 1.17 – 1.07
1
3
(m, 1H), 1.00 – 0.92 (m, 1H) ppm; C NMR (150 MHz, CDCl ): δ = 134.9 (d, J = 12.1 Hz),
3
1
4
31.6 (br s), 131.3 (d, J = 44.0 Hz), 130.7 (d, J = 2.3 Hz), 128.5 (d, J = 10.5 Hz), 84.7 (br s),
8.5 (s), 46.9 (s), 41.2 (s), 32.2 (s), 31.9 (s), 30.5 (s), 28.7 (br s), 18.0 (s) ppm; IR (ATR):
–1
ṽmax = 2930, 1434, 1090, 998, 981, 758, 743, 703, 694, 688 cm ; HRMS (ESI+): m/z for
+
+
C H PPd [M–I] : calcd.: 501.0958, found: 501.0959.
28
28
3
,7
Tricyclo[4.3.1.0 ]dec-4-ene-2-ylbistriphenylphosphinepalladium(II) tetrafluoroborate
13). A mixture of Pd-complex 11 (79.7 mg, 0.137 mmol, 1.00 eq.), AgBF (26.7 mg,
(
4
0
.137 mmol, 1.00 eq.) and PPh (35.9 mg, 0.137 mmol, 1.00 eq.) in CH Cl (15.0 mL) was
3 2 2
stirred at room temperature for 1.5 h and was then filtered. Et O (15.0 mL) was added to the
2
filtrate and the mixture was allowed to stand to facilitate crystallization. Silver bromide
deposited on the bottom of the flask. The supernatant solution was decanted and concentrated
in vacuo. Crystallization of the residue from CH Cl /Et O afforded yellow crystals of
2
2
2
complex 13 (80 mg, 69%) that were suitable for single crystal X-ray diffraction.
1
R = 0.43 (CH Cl : MeOH = 95 : 5); mp 117 °C (dec.); H NMR (600 MHz, CDCl ): δ = 7.51
f
2
2
3
– 7.44 (m, 6H), 7.43 – 7.35 (m, 6H), 7.34 – 7.27 (m, 12H), 7.13 – 7.07 (m, 6H), 5.99 – 5.92
m, 1H), 5.82 – 5.74 (m, 1H), 3.53 – 3.43 (m, 1H), 2.73 – 2.64 (m, 1H), 2.49 – 2.41 (m, 1H),
(
2
1
.32 – 2.22 (m, 1H), 1.97 – 1.87 (m, 1H), 1.60 – 1.50 (m, 2H), 1.49 – 1.40 (m, 1H), 1.40 –
13
.33 (m, 1H), 1.29 – 1.20 (m, 1H), 0.97 – 0.86 (m, 1H) ppm; C NMR (150 MHz, CDCl ):
3
δ = 134.3 (d, J = 12.4 Hz), 133.5 (d, J = 12.4 Hz), 131.6 (s), 130.8 (s), 130.4 (d, J = 30.4 Hz),
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4
29.5 (d, J = 30.4 Hz), 129.3 (d, J = 8.6 Hz), 129.1, 129.0 (d, J = 8.6 Hz), 90.0 (br s), 47.8 (s),
7.0 (s), 41.1 (s), 33.1 (s), 31.9 (s), 30.9 (br s), 29.9 (br s), 17.9 (s) ppm; IR (ATR): ṽmax
=
–
1
+
2926, 1481, 1434, 1094, 1056, 742, 695 cm ; HRMS (ESI+): m/z for C H PPd [M–PPh –
28
28
3
+
BF ] : calcd.: 501.0958, found: 501.0960.
4
0
1
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8
9
0
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6
7
8
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0
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8
9
0
Cyclization of Alkenyl Bromide 9 with Catalytic Amounts of Palladium. To a round
bottom flask were added Pd(OAc)2 (106 mg, 0.470 mmol 0.100 eq.),
1,3-bis(diphenylphosphino)propane (236 mg, 0.940 mmol, 0.200 eq.) and potassium formate
1.19 g, 14.1 mmol, 3.00 eq.). The flask was evacuated and refilled with argon three times.
The salts were dissolved in degassed DMF (250 mL) and alkenyl bromide 9 (1.00 g,
.70 mmol, 1.00 eq.) was added. The reaction mixture was transferred to a preheated oil bath
(
4
and stirred at 60 °C for 24 h. During the reaction the color of the mixture turned from yellow
to black. The reaction mixture was allowed to cool to room temperature and was diluted with
H O (200 mL) and pentane (200 mL) and the resulting mixture was stirred for 15 min at room
2
temperature. The organic layer was separated and the aqueous layer was extracted with n-
pentane (3 x 50 mL). The combined organic layer was dried (Na SO ) and concentrated in
2
4
vacuo (at room temperature). Purification of the residue by flash column chromatography
(
silica, n-pentane) afforded cyclopropane 15 as a colorless solid (33 mg, 5%), isotwistene 16
196 mg, 28%) as a colorless solid and vinyl bicyclooctene 17 (400 mg, 52%) as a colorless
(
oil.
Tetracyclo[4.4.0.0 .0 ]decane (15)
R = 0.88 (hexanes); mp 117 – 121 °C; H NMR (600 MHz, CDCl ): δ = 2.06 – 2.01 (m, 1H),
3
,8 5,7
1
f
3
1
1
1
.97 – 1.92 (m, 1H), 1.81 – 1.76 (m, 2H), 1.70 – 1.64 (m, 1H), 1.63 – 1.56 (m, 1H), 1.50 –
.43 (m, 2H), 1.42 – 1.35 (m, 1H), 1.29 – 1.22 (m, 2H), 1.15 – 1.07 (m, 2H), 0.80 – 0.74 (m,
1
3
H) ppm; C NMR (150 MHz, CDCl ): δ = 35.6, 33.2, 33.1, 33.0, 27.4, 25.1, 19.6, 18.4,
3
–1
17.1, 16.3 ppm; IR (ATR): ṽmax = 2928, 2861, 778, 752, 735 cm ; HRMS (EI): m/z for
+
+
C H [M] : calcd.: 134.1090, found: 134.1087.
10
14
3,7
Tricyclo[4.3.1.0 ]dec-4-ene – isotwistene (16)
1
R = 0.82 (hexanes); mp 96 – 98 °C; H NMR (600 MHz, CDCl ): δ = 6.10 – 6.07 (m, 2H),
f
3
2.29 – 2.24 (m, 2H), 2.09 – 2.05 (m, 1H), 1.83 – 1.77 (m, 3H), 1.58 – 1.54 (m, 2H), 1.47 –
1
3
1
.36 (m, 4H) ppm; C NMR (75 MHz, CDCl ): δ = 140.2, 40.3, 39.4, 29.7, 28.5, 28.4, 19.7
3
–1
ppm; IR (ATR): ṽmax = 2924, 2856, 1450, 1345, 966, 907, 819, 785, 726 cm ; HRMS (EI):
+
14
+
m/z for C H [M] : calcd.: 134.1090, found: 134.1097.
10
5
-endo-Vinylbicyclo[2.2.2]oct-2-ene (17)
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5
1
R = 0.75 (hexanes); H NMR (300 MHz, CDCl ): δ = 6.32 (ddd, J = 7.9, 6.6, 1.1 Hz, 1H),
f
3
6
.22 – 6.14 (m, 1H), 5.61 (ddd, J = 17.2, 10.1, 8.1 Hz, 1H), 4.92 (ddd, J = 17.2, 2.0, 1.1 Hz,
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1H), 4.83 (ddd, J = 10.1, 2.0 Hz, 0.9 Hz, 1H), 2.57 – 2.51 (m, 1H), 2.51 – 2.44 (m, 1H), 2.44
–
2
4
2.37 (m, 1H), 1.82 (ddd, J = 12.4, 9.5, 2.7 Hz, 1H), 1.66 – 1.44 (m, 2H), 1.41 – 1.23 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
H), 1.16 – 1.04 (m, 1H) ppm; C NMR (75 MHz, CDCl ): δ = 145.6, 135.0, 132.2, 111.8,
3
2.6, 35.9, 33.8, 30.0, 26.3, 24.6 ppm; IR (ATR): ṽmax = 2927, 2861, 994, 906, 857, 819, 727,
–
1
+
+
708, 676, 668 cm ; HRMS (EI): m/z for C H [M] : calcd.: 134.1090, found: 134.1092.
10
14
5
-Methylbicyclo[2.2.2]oct-5-ene-2-endo-carbaldehyde (S2). To a solution of methyl-
37
cyclohexadiene S1
(4.54 mL, 3.77 g, 40.0 mmol, 1.00 eq.) in 2-methoxyethyl ether
(20.0 mL) at room temperature was added successively acrolein (4.00 mL, 3.36 g, 60.0 mmol,
1.50 eq.) and BF ·OEt (0.740 mL, 0.852 g, 6.00 mmol, 0.300 eq.). The reaction mixture was
3
2
stirred at room temperature for 20 h. The mixture was diluted with H O (50 mL) and the
2
aqueous layer was extracted with Et O (3 x 50 mL). The combined organic layer was washed
2
with H O (3 x 50 mL), dried (Na SO ) and concentrated in vacuo. Purification of the residue
2
2
4
by flash column chromatography (silica, n-pentane : Et O = 95 : 5) afforded bicycloaldehyde
2
S2 (3.83 g, 64%) as a colorless oil.
1
R = 0.62 (hexanes : EtOAc = 9 : 1); H NMR (300 MHz, CDCl ): δ = 9.42 (d, J = 1.6 Hz,
f
3
1
H), 5.72 – 5.66 (m, 1H), 2.90 – 2.82 (m, 1H), 2.54 – 2.46 (m, 1H), 2.45 – 2.39 (m, 1H), 1.76
1
3
(
d, J = 1.7 Hz, 3H), 1.74 – 1.45 (m, 4H), 1.41 – 1.22 (m, 2H) ppm; C NMR (75 MHz,
CDCl ): δ = 204.6, 145.1, 123.1, 52.0, 35.1, 31.7, 26.7, 26.4, 24.8, 20.3 ppm; IR (ATR):
3
–1
ṽmax = 3429, 2935, 2870, 1711, 1452, 1375, 1353, 1176, 1095, 1046, 995, 967, 923 cm ;
+
+
HRMS (EI): m/z for C H O [M] : calcd.: 150.1039, found: 150.1037.
1
0
14
5
-(endo-(Z)-2-Bromoalkenyl)-2-methylbicyclo[2.2.2]oct-2-ene (18). To a solution of
(bromomethyl)triphenylphosphonium bromide (9.59 g, 22.0 mmol, 1.10 eq.) in THF
(91.0 mL) at 78 °C was added KOt-Bu (2.47 g, 22.0 mmol, 1.10 eq.). The resulting yellow
reaction mixture was stirred at 78 °C for 30 min, after which time DMPU (11.3 mL, 12.0 g,
9
4.0 mmol, 4.70 eq.) and aldehyde S2 (3.00 g, 20.0 mmol, 1.00 eq.) were added successively.
The mixture was stirred for an additional 3 h at 78 °C and was then diluted with hexanes
300 mL) and filtered over celite. The residue was washed with hexanes (300 mL) and the
(
combined filtrates were concentrated in vacuo. Purification of the residue by flash column
chromatography (silica, hexanes : EtOAc = 1000 : 1) afforded alkenyl bromide 18 (3.74 g,
8
2%) as a colorless oil.
1
R = 0.73 (hexanes); H NMR (300 MHz, CDCl ): δ = 5.95 (dd, J = 6.8, 0.8 Hz, 1H), 5.81 (dd,
f
3
J = 8.9, 6.8 Hz, 1H), 5.78 – 5.73 (m, 1H), 2.87 – 2.75 (m, 1H), 2.42 – 2.35 (m, 1H), 2.35 –
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1
.30 (m, 1H), 1.91 (ddd, J = 12.5, 9.6, 2.7 Hz, 1H), 1.80 (d, J = 1.7 Hz, 3H), 1.65 – 1.54 (m,
H), 1.53 – 1.43 (m, 1H), 1.32 – 1.18 (m, 2H), 0.98 (dddd, J = 12.5, 5.0, 2.8, 2.8 Hz, 1H)
1
3
ppm; C NMR (75 MHz, CDCl ) δ = 144.2, 142.0, 124.2, 104.5, 39.6, 35.3, 34.9, 33.4, 26.7,
3
2
8
2
4.2, 20.4 ppm; IR (ATR): ṽmax = 2930, 2861, 1443, 1322, 1290, 1277, 981, 940, 912, 854,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1
+
+
08, 799, 707, 663 cm ; HRMS (EI): m/z for C H Br [M] : calcd.: 226.0352, found:
11
15
26.0345.
2-Methylbicyclo[2.2.2]oct-5-en-2-endo-carbaldehyde
(S3).
To
a
solution
of
cyclohexadiene 7 (3.73 mL, 3.21 g, 40.0 mmol, 2.00 eq.) in 2-methoxyethyl ether (20.0 mL)
at room temperature was added successively methacrolein (1.66 mL, 1.40 g, 20.0 mmol,
1
.00 eq.) and BF ·OEt (0.370 mL, 0.426 g, 3.00 mmol, 0.150 eq.). The reaction mixture was
3 2
stirred at room temperature for 20 h and was then quenched by addition of K HPO (522 mg,
2
4
3.00 mmol, 0.150 eq.). The mixture was diluted with H O (25 mL) and the aqueous layer was
2
extracted with Et O (3 x 30 mL). The combined organic layer was washed with H O (3 x
2
2
2
5 mL), dried (Na SO ) and concentrated in vacuo. Purification of the residue by flash
2 4
column chromatography (silica, n-pentane : Et O = 97 : 3) afforded bicycloaldehyde S3
2
(1.64 g, 54%) as a colorless oil.
1
R = 0.53 (hexanes : EtOAc = 9 : 1); H NMR (400 MHz, CDCl ): δ = 9.30 (s, 1H), 6.26 –
f
3
6
1
.19 (m, 2H), 2.62 – 2.55 (m, 1H), 2.49 – 2.43 (m, 1H), 2.03 – 1.96 (m, 1H), 1.92 – 1.84 (m,
1
3
H), 1.56 – 1.47 (m, 1H), 1.30 – 1.10 (m, 6H) ppm; C NMR (100 MHz, CDCl ): δ = 205.7,
3
135.2, 133.6, 50.0, 36.1, 35.6, 30.6, 25.2, 21.3, 20.3 ppm; IR (ATR): ṽmax = 2943, 2866, 1721,
–
1
+
+
1
449, 1368, 1074, 1058, 1041, 900, 812, 693, 668 cm ; HRMS (EI): m/z for C H O [M] :
10 14
calcd.: 150.1039, found: 150.1048.
-(endo-(Z)-2-Bromoalkenyl)-5-methylbicyclo[2.2.2]oct-2-ene (19). To a solution of
bromomethyl)triphenylphosphonium bromide (3.48 g, 7.99 mmol, 1.10 eq.) in THF
5
(
(33.0 mL) at 78 °C was added KOt-Bu (0.896 g, 7.99 mmol, 1.10 eq.). The resulting yellow
reaction mixture was stirred at 78 °C for 15 min, after which time DMPU (4.11 mL, 4.37 g,
3
4.1 mmol, 4.70 eq.) and aldehyde S3 (1.09 g, 7.26 mmol, 1.00 eq.) were added successively.
The mixture was stirred for an additional 3 h at 78 °C and was then diluted with hexanes
200 mL) and filtered over celite. The residue was washed with hexanes (200 mL) and the
(
combined filtrates were concentrated in vacuo. Purification of the residue by flash column
chromatography (silica, hexanes : EtOAc = 100 : 1) afforded alkenyl bromide 19 (1.27 g,
7
7%) as a colorless oil.
1
R = 0.85 (hexanes : EtOAc = 9 : 1); H NMR (300 MHz, CDCl ): δ = 6.37 – 6.24 (m, 2H),
f
3
6
.20 (d, J = 7.6 Hz, 1H), 5.92 (d, J = 7.6 Hz, 1H), 2.57 – 2.45 (m, 2H), 1.98 – 1.84 (m, 2H),
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.57 (dd, J = 12.9, 2.4 Hz, 1H), 1.53 – 1.40 (m, 1H), 1.37 (s, 3H), 1.30 – 1.05 (m, 2H) ppm;
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
C NMR (75 MHz, CDCl ): δ = 146.9, 135.0, 135.0, 103.8, 45.1, 41.1, 40.2, 31.5, 25.5, 24.4,
3
20.9 ppm; IR (ATR): ṽmax = 2940, 2922, 2862, 1608, 1443, 1367, 1312, 911, 811, 746, 702,
–
1
+
+
6
1
2
92, 671, 641, 615, 566 cm ; HRMS (EI): m/z for C H [M–Br] : calcd.: 147.1168, found:
11 15
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
47.1159.
,5-Dimethylbicyclo[2.2.2]oct-5-ene-2-endo-carbaldehyde (S4). To
a
solution of
methylcyclohexadiene S1 (2.27 mL, 1.88 g, 20.0 mmol, 1.00 eq.) in 2-methoxyethyl ether
20.0 mL) at room temperature was added successively methacrolein (2.48 mL, 2.10 g,
0.0 mmol, 1.50 eq.) and BF ·OEt (0.370 mL, 0.426 g, 3.00 mmol, 0.300 eq.). The reaction
(
3
3
2
mixture was stirred at room temperature for 20 h. The mixture was diluted with H O (25 mL)
2
and the aqueous layer was extracted with Et O (3 x 25 mL). The combined organic layer was
2
washed with H O (3 x 25 mL), dried (Na SO ) and concentrated in vacuo. Purification of the
2
2
4
residue by flash column chromatography (silica, n-pentane : Et O = 95 : 5) afforded
2
bicycloaldehyde S4 (1.24 g, 38%) as a colorless oil.
1
R = 0.44 (n-pentane : Et O = 95 : 5); H NMR (600 MHz, CDCl ): δ = 9.30 (s, 1H), 5.82 –
f
2
3
5.79 (m, 1H), 2.40 – 2.37 (m, 1H), 2.37 – 2.34 (m, 1H), 2.02 (ddd, J = 13.0, 3.2, 3.2 Hz, 1H),
.87 (dddd, J = 12.8, 9.6, 3.1, 3.1 Hz, 1H), 1.73 (d, J = 1.7 Hz, 3H), 1.50 (dddd,
1
J = 12.0, 9.6, 4.7, 2.4 Hz, 1H), 1.26 (ddddd, J = 12.0, 9.9, 3.2, 3.2, 3.1 Hz, 1H), 1.17 (dddd,
J = 12.8, 9.9, 4.8, 3.2 Hz, 1H), 1.11 (s, 3H), 1.10 (dd, J = 13.0, 2.4 Hz, 1H) ppm;
1
3
C NMR (150 MHz, CDCl ): δ = 206.0, 144.1, 125.6, 50.6, 36.8, 36.3, 35.1, 25.0, 21.3, 21.0,
3
–
1
2
0.2 ppm; IR (ATR): ṽmax = 2930, 2869, 1713, 1447, 1377, 1162, 1103, 1067, 990, 756 cm ;
+
+
HRMS (EI): m/z for C H O [M] : calcd.: 164.1196, found: 164.1204.
1
1
16
5
-(endo-(Z)-2-Bromoalkenyl)-2,5-dimethylbicyclo[2.2.2]oct-2-ene (20). To a solution of
(bromomethyl)triphenylphosphonium bromide (3.60 g, 8.25 mmol, 1.10 eq.) in THF
(34.0 mL) at 78 °C was added KOt-Bu (0.926 g, 8.25 mmol, 1.10 eq.). The resulting yellow
reaction mixture was stirred at 78 °C for 30 min, after which time DMPU (4.25 mL, 4.52 g,
3
5.3 mmol, 4.70 eq.) and aldehyde S4 (1.23 g, 7.50 mmol, 1.00 eq.) were added successively.
The mixture was stirred for an additional 3 h at 78 °C and was then diluted with hexanes
600 mL) and filtered over celite. The residue was washed with hexanes (600 mL) and the
(
combined filtrates were concentrated in vacuo. Purification of the residue by flash column
chromatography (silica, hexanes : EtOAc = 1000 : 1) afforded alkenyl bromide 20 (620 mg,
3
5%) as a colorless oil.
1
R = 0.91 (hexanes : EtOAc = 9 : 1); H NMR (300 MHz, CDCl ): δ = 6.20 (d, J = 7.6 Hz,
f
3
1
H), 5.94 – 5.89 (m, 1H), 5.90 (d, J = 7.6 Hz, 1H), 2.39 – 2.33 (ddd, J = 6.2, 2.9, 2.9 Hz, 1H),
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1
.33 – 2.26 (m, 1H), 1.97 – 1.81 (m, 2H), 1.76 (d, J = 1.7 Hz, 3H), 1.55 (dd, J = 12.9, 2.4 Hz,
H), 1.44 (dddd, J = 11.7, 9.4, 5.1, 2.9 Hz, 1H), 1.35 (s, 3H), 1.24 (ddddd,
1
3
J = 11.7, 9.4, 3.2, 3.2, 3.2 Hz, 1H), 1.16 – 1.03 (m, 1H) ppm; C NMR (75 MHz, CDCl ): δ =
3
1
47.2, 143.5, 127.0, 103.6, 44.5, 41.8, 40.7, 37.1, 25.6, 23.9, 21.8, 20.4 ppm; IR (ATR):
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1
ṽmax = 2919, 2861, 1609, 1443, 1373, 1313, 1113, 915, 820, 800, 742, 692 cm ; HRMS (EI):
+
+
m/z for C H Br [M] : calcd.: 240.0508, found: 240.0515.
12
17
Cyclization of Alkenyl Bromide 18 with Catalytic Amounts of Palladium. To a round
bottom flask were added Pd(OAc) (12.3 mg, 0.055 mmol, 0.025 eq.), n-Bu NCl (611 mg,
2
4
2
.20 mmol, 1.00 eq.) and potassium formate (555 mg, 6.60 mmol, 3.00 eq.). The flask was
evacuated and refilled with argon three times. The salts were dissolved in degassed DMF
(132 mL) and alkenyl bromide 18 (0.500 g, 2.20 mmol, 1.00 eq.) was added. The reaction
mixture was transferred to a preheated oil bath and stirred at 70 °C for 24 h. During the
reaction the color of the mixture turned from yellow to black. The reaction mixture was
allowed to cool to room temperature and was diluted with H O (110 mL) and pentane
2
(
110 mL) and the resulting mixture was stirred for 15 min at room temperature. The organic
layer was separated and the aqueous layer was extracted with n-pentane (3 x 110 mL). The
combined organic layer was dried (Na SO ) and concentrated in vacuo (at room temperature).
2
4
Purification of the residue by flash column chromatography (silica, n-pentane) afforded
methylisotwistene 21 (80 mg, 25%) as a colorless oil and vinyl bicyclooctene 22 (35 mg,
11%) contaminated with methylisotwistene 21 as a colorless oil.
3
,7
2
-Methyltricyclo[4.3.1.0 ]dec-4-ene (21)
1
R = 0.78 (hexanes); H NMR (600 MHz, CDCl ): δ = 6.09 (dd, J = 5.7, 3.0 Hz, 1H), 6.07 (dd,
f
3
J = 5.7, 2.9 Hz, 1H), 2.27 – 2.23 (m, 1H), 2.08 – 2.04 (m, 1H), 1.87 – 1.79 (m, 1H), 1.79 –
.74 (m, 3H), 1.70 – 1.67 (m, 1H), 1.67 – 1.62 (m, 1H), 1.48 – 1.44 (m, 2H), 1.31 – 1.23 (m,
1
1
3
1H), 0.94 (d, J = 7.2 Hz, 3H) ppm; C NMR (150 MHz, CDCl ): δ = 140.5, 139.6, 47.2, 41.0,
3
3
1
7
8.5, 34.6, 32.6, 31.6, 21.1, 20.7, 19.2 ppm; IR (ATR): ṽmax = 3403, 2924, 2864, 1713, 1454,
404, 1373, 1352, 1266, 1187, 1131, 1104, 1095, 1067, 1041, 1018, 994, 927, 913, 885, 853,
–
1
+
+
53, 666 cm ; HRMS (EI): m/z for C H [M] : calcd.: 148.1247, found: 148.1243.
1
1
16
2-Methyl-5-endo-vinylbicyclo[2.2.2]oct-2-ene (22)
1
R = 0.68 (hexanes); H NMR (600 MHz, CDCl ): δ = 5.77 – 5.74 (m, 1H), 5.56 (ddd,
f
3
J = 17.2, 10.2, 8.2 Hz, 1H), 4.87 (ddd, J = 17.2, 2.0, 1.1 Hz, 1H), 4.79 (ddd,
J = 10.2, 2.0, 0.9 Hz, 1H), 2.37 – 2.34 (m, 1H), 2.34 – 2.31 (m, 1H), 2.31 – 2.28 (m, 1H), 1.79
(d, J = 1.8 Hz, 3H), 1.78 – 1.74 (m, 1H), 1.57 – 1.51 (m, 1H), 1.48 – 1.43 (m, 1H), 1.27 –
1
3
1
.21 (m, 2H), 1.08 – 1.02 (m, 1H) ppm; C NMR (150 MHz, CDCl ): δ = 145.9, 143.3,
3
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24.3, 111.5, 43.4, 36.3, 35.6, 33.5, 27.2, 24.3, 20.3 ppm; IR (ATR): ṽmax = 2926, 2862, 1710,
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
–
1
1
453, 1375, 1356, 1335, 1168, 1102, 1067, 1041, 995, 967, 913, 876, 852, 805, 733 cm ;
+
16
+
HRMS (EI): m/z for C H [M] : calcd.: 148.1247, found: 148.1253.
1
1
5
-Methyl-5-endo-vinylbicyclo[2.2.2]oct-2-ene (23). To a round bottom flask were added
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pd(OAc) (2.8 mg, 0.013 mmol, 0.025 eq.), n-Bu NCl (139 mg, 0.500 mmol, 1.00 eq.) and
2
4
potassium formate (126 mg, 1.50 mmol, 3.00 eq.). The flask was evacuated and refilled with
argon three times. The salts were dissolved in degassed DMF (30.0 mL) and alkenyl bromide
1
9 (114 mg, 0.500 mmol, 1.00 eq.) was added. The reaction mixture was transferred to a
preheated oil bath and stirred at 70 °C for 24 h. During the reaction the color of the mixture
turned from yellow to black. The reaction mixture was allowed to cool to room temperature
and was diluted with H O (30 mL) and pentane (30 mL) and the resulting mixture was stirred
2
for 15 min at room temperature. The organic layer was separated and the aqueous layer was
extracted with n-pentane (3 x 25 mL). The combined organic layer was dried (Na SO ) and
2
4
concentrated in vacuo (at room temperature). Purification of the residue by flash column
chromatography (silica, n-pentane) afforded vinyl bicyclooctene 23 (16 mg, 22%) as a
colorless oil.
1
R = 0.74 (hexanes); H NMR (400 MHz, CDCl ): δ = 6.28 (ddd, J = 8.0, 6.5, 1.3 Hz, 1H),
f
3
6
.17 (ddd, J = 8.0, 6.0, 1.2 Hz, 1H), 5.77 (dd, J = 17.5, 10.8 Hz, 1H), 4.79 (dd,
J = 17.5, 1.4 Hz, 1H), 4.78 (dd, J = 10.7, 1.4 Hz, 1H), 2.51 (dddddd,
J = 6.0, 3.5, 3.5, 2.2, 2.2, 1.3 Hz, 1H), 2.17 (dddd, J = 6.5, 2.8, 2.8, 1.2 Hz, 1H), 1.91 (dddd,
J = 12.7, 9.7, 3.0, 2.8 Hz, 1H), 1.52 – 1.43 (m, 2H), 1.31 – 1.20 (m, 2H), 1.15 (s, 3H), 1.16 –
1
3
1
.04 (m, 1H) ppm; C NMR (100 MHz, CDCl ): δ = 150.9, 135.7, 132.4, 108.9, 41.0, 40.4,
3
3
9.6, 31.1, 27.1, 24.2, 21.8 ppm; IR (ATR): ṽmax = 2926, 2862, 1634, 1448, 1366, 1005, 904,
–
1
+
+
8
86, 816, 810, 731, 716, 689 cm ; HRMS (EI): m/z for C H [M] : calcd.: 148.1247,
11 16
found: 148.1240.
2
,5-Dimethyl-5-endo-vinylbicyclo[2.2.2]oct-2-ene (24). To a round bottom flask were added
Pd(OAc) (2.8 mg, 0.013 mmol. 0.025 eq.), n-Bu NCl (139 mg, 0.500 mmol, 1.00 eq.) and
2
4
potassium formate (126 mg, 1.50 mmol, 3.00 eq.). The flask was evacuated and refilled with
argon three times. The salts were dissolved in degassed DMF (30.0 mL) and alkenyl bromide
2
0 (121 mg, 0.500 mmol, 1.00 eq.) was added. The reaction mixture was transferred to a
preheated oil bath and stirred at 70 °C for 24 h. During the reaction the color of the mixture
turned from yellow to black. The reaction mixture was allowed to cool to room temperature
and was diluted with H O (30 mL) and pentane (30 mL) and the resulting mixture was stirred
2
for 15 min at room temperature. The organic layer was separated and the aqueous layer was
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extracted with n-pentane (3 x 25 mL). The combined organic layer was dried (Na SO ) and
2
4
concentrated in vacuo (at room temperature). Purification of the residue by flash column
chromatography (silica, n-pentane) afforded vinyl bicyclooctene 24 (35 mg, 43%) as a
colorless oil.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
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7
8
9
0
1
2
3
4
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7
8
9
0
1
R = 0.75 (hexanes); H NMR (400 MHz, CDCl ): δ = 5.88 – 5.85 (ddq, J = 6.7, 2.1, 1.7 Hz,
f
3
1
H), 5.77 (dd, J = 17.3, 10.9 Hz, 1H), 4.80 – 4.74 (m, 2H), 2.28 (ddddd,
J = 3.8, 3.8, 2.1, 2.1, 2.1 Hz, 1H), 2.06 (ddd, J = 6.7, 2.8, 2.8 Hz, 1H), 1.89 (dddd,
J = 12.7, 9.6, 3.0, 3.0 Hz, 1H), 1.76 (d, J = 1.7 Hz, 3H), 1.50 – 1.41 (m, 2H), 1.31 – 1.20 (m,
13
2
1
H), 1.13 (s, 3H), 1.13 – 1.06 (m, 1H) ppm; C NMR (100 MHz, CDCl ): δ = 151.2, 140.7,
3
27.7, 108.6, 41.0, 40.6, 40.2, 36.7, 26.9, 23.8, 22.6, 20.2 ppm; IR (ATR): ṽmax = 2923, 2861,
–1
+
+
1446, 906, 887, 733 cm ; HRMS (EI): m/z for C H
18
[M] : calcd.: 162.1403, found:
1
2
162.1383.
-Methyltricyclo[4.3.1.0 ]dec-4-ene-2-yltriphenylphosphinepalladium(II) bromide (25).
To a solution of Pd(PPh ) (497 mg, 0.430 mmol, 1.00 eq.) in toluene (3.00 mL) was added
3
,7
6
3
4
Z-alkenyl bromide 19 (97.7 mg, 0.430 mmol, 1.00 eq.) by syringe. The yellow reaction
mixture was heated to 80 °C for 2 h. The mixture was allowed to cool to room temperature
and Et O (50 mL) was added, precipitating a white solid. The precipitate was filtered off and
2
the filtrate was allowed to stand. Upon slow evaporation of the solvent palladium complex 25
(45 mg, 18%) crystallized in the form of yellow platelets. Crystals suitable for single crystal
X-ray diffraction could be obtained from this mixture.
1
mp 158 °C (dec.); H NMR (600 MHz, CDCl ): δ = 7.75 – 7.69 (m, 6H), 7.46 – 7.38 (m, 9H),
3
6
1
.61 – 6.56 (m, 1H), 6.15 – 6.12 (m, 1H), 3.23 – 3.17 (m, 1H), 3.04 (dd, J = 13.0, 4.1 Hz,
H), 1.83 – 1.78 (m, 1H), 1.61 – 1.52 (m, 1H), 1.47 – 1.32 (m, 3H), 1.27 – 1.21 (m, 1H), 1.16
1
3
(
s, 3H), 0.99 – 0.89 (m, 2H) ppm; C NMR(150 MHz, CDCl ): δ = 136.9 (d, J = 10.0 Hz),
3
134.7 (d, J = 12.3 Hz), 131.0 (d, J = 43.9 Hz), 130.7 (d, J = 2.4 Hz), 128.5 (d, J = 10.4 Hz),
5.1 (d, J = 13.3 Hz), 52.6 (s), 50.2 (s), 45.5 (d, J = 2.4 Hz), 41.4 (s), 32.6 (s), 30.3 (d,
J = 5.1 Hz), 26.7 (d, J = 7.4 Hz), 23.4 (s), 16.0 (s) ppm; IR (ATR): ṽmax = 2361, 2339, 1436,
8
–1
+
+
7
43, 739, 694, 668 cm ; HRMS (ESI+): m/z for C H PPd [M–Br] : calcd.: 515.1114,
29 30
found: 515.1117.
(Z)-2-(2-methylbicyclo[2.2.2]oct-2-en-5-endo-yl)vinylbis(triphenylphosphine)-
palladium(II) bromide (26). To a solution of Pd(PPh ) (994 mg, 0.860 mmol, 1.00 eq.) in
3
4
benzene (6.00 mL) was added Z-alkenyl bromide 18 (195 mg, 0.860 mmol, 1.00 eq.) by
syringe. The yellow reaction mixture was heated to 65 °C for 2 h. The mixture was allowed to
cool to room temperature and Et O (50 mL) was added, precipitating a white solid. The
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precipitate was filtered off and the filtrate was allowed to stand. Upon slow evaporation of the
solvent palladium complex 26 (290 mg, 57%) crystallized in the form of yellow platelets.
Crystals suitable for single crystal X-ray diffraction could be obtained from this mixture. For
NMR analysis the reaction was run in C D in a NMR tube resulting in a mixture of starting
6
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
material and product in the NMR.
1
mp 123 °C (dec.); H NMR (400 MHz, C D ): δ = 7.99 – 7.92 (m, 12H), 7.44 (m, 18H), 5.75
6
6
(td, J = 10.4, 7.2 Hz, 1H), 5.54 (dq, J = 6.7, 1.7 Hz, 1H), 4.95 (ddt, J = 9.4, 7.3, 4.7 Hz, 1H),
3
1
1
.07 (dddd, J = 9.4, 9.3, 4.8, 2.0 Hz, 1H), 2.14 – 2.06 (m, 1H), 2.02 – 1.94 (m, 1H), 1.88 –
.78 (m, 1H), 1.60 (d, J = 1.7 Hz, 3H), 1.57 – 1.50 (m, 1H), 1.37 (ddd, J = 12.4, 9.3, 2.7 Hz,
H), 1.32 – 1.24 (m, 2H), 0.64 (dddd, J = 12.4, 4.8, 2.6, 2.6 Hz, 1H) ppm;
C NMR (100 MHz, C D ): δ = 144.2, 142.7, 137.7, 135.9, 134.3, 134.1, 132.5 (d,
1
3
6
6
J = 44.0 Hz), 125.0, 47.0, 36.2, 36.1, 34.7, 27.8, 24.8, 20.4 ppm; IR (ATR): ṽmax = 1478,
–
1
1
434, 1309, 1262, 1183, 1094, 1027, 998, 751, 741, 703, 689, 677 cm ; HRMS (ESI+): m/z
+
+
for C H PPd [M–PPh –Br] : calcd.: 515.1114, found: 515.1117.
2
9
30
3
3
8
Methylbicyclo[2.2.2]oct-5-ene-2-endo-carboxylate (S5). Within a glovebox bis (trifluoro-
methane)sulfonamide (26.4 g, 93.8 mmol, 0.150 eq.) was weighed into a one necked flask.
Allyltrimethylsilane (29.8 mL, 21.4 g, 188 mmol, 0.300 eq.) was added outside of the
glovebox at 0 °C with stirring and stirring was continued at room temperature until the end of
gas evolution. The reaction mixture was concentrated for 1 h under high vacuum. The residue
was dissolved in toluene (1.25 L) and methyl acrylate (56.3 mL, 53.8 g, 0.625 mol, 1.00 eq.)
and cyclohexadiene 7 (89.4 mL, 75.1 g, 0.938 mol, 1.50 eq.) were added successively at 0 °C
to the solution. The reaction mixture was stirred at 0 °C for 3.5 h, after which time 880 mL of
a saturated aqueous NaHCO solution were added to the violet reaction mixture. The resulting
3
mixture was stirred at room temperature for 1 h during which time it turned yellow. The
organic layer was separated and the aqueous layer was extracted with CH Cl (3 x 600 mL).
2
2
The combined organic layer was dried (MgSO ) and concentrated in vacuo. Purification of the
4
residue by flash column chromatography (silica, hexanes : EtOAc = 9 : 1) afforded
bicycloester S5 as a colorless oil (104 g, 99%).
1
R = 0.44 (hexanes : EtOAc = 9 : 1); H NMR (300 MHz, CDCl ): δ = 6.35 – 6.27 (m, 1H),
f
3
6
1
1
2
.18 – 6.11 (m, 1H), 3.63 – 3.62 (s, 3H), 2.96 – 2.88 (m, 1H), 2.67 – 2.56 (m, 2H), 1.79 –
13
.64 (m, 2H), 1.60 – 1.45 (m, 2H), 1.33 – 1.19 (m, 2H) ppm; C NMR (75 MHz, CDCl ): δ =
3
76.1, 135.3, 131.5, 51.8, 42.8, 32.6, 30.0, 29.5, 25.5, 24.5 ppm; IR (ATR): ṽmax = 2943,
866, 1733, 1453, 1434, 1374, 1351, 1320, 1235, 1195, 1171, 1081, 1054, 1031, 889, 698
–
1
+
+
cm ; HRMS (EI): m/z for C H O [M] : calcd.: 166.0994, found: 166.0982.
1
0
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5
-endo-Hydroxymethylbicyclo[2.2.2]oct-2-ene (S6). To a solution of LiAlH (2.50 g,
4
6
6.0 mmol, 0.600 eq.) in Et O (130 mL) was added dropwise a solution of bicycloester S5
2
(18.3 g, 110 mmol, 1.00 eq.) in Et O (25.0 mL). After complete addition the reaction mixture
2
was heated to 35 °C for 16 h and was then cooled to 0 °C. Excess LiAlH was hydrolyzed by
4
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dropwise addition of H O. Rochelle salt was added until a homogeneous solution was
2
obtained. The aqueous layer was extracted with Et O (4 x 50 mL) and the combined organic
2
layer was washed with H O (75 mL), brine (75 mL), dried (Na SO ) and concentrated in
2
2
4
vacuo. Purification of the residue by flash column chromatography (silica, hexanes : Et O = 2
2
:
1) afforded bicyclooctenol S6 (14.3 g, 94%) as a colorless oil.
1
R = 0.44 (hexanes : EtOAc = 1 : 1); H NMR (300 MHz, CDCl ): δ = 6.27 (ddd,
f
3
J = 8.0, 6.6, 1.2 Hz, 1H), 6.16 – 6.09 (m, 1H), 3.28 – 3.21 (m, 2H), 2.63 – 2.57 (m, 1H), 2.53
– 2.45 (m, 1H), 1.93 – 1.86 (m, 1H), 1.67 (ddd, J = 12.2, 9.5, 2.7 Hz, 1H), 1.55 – 1.45 (m,
1
3
2
1
1
H), 1.32 – 1.21 (m, 2H), 0.80 – 0.70 (m, 1H) ppm; C NMR (75 MHz, CDCl ): δ = 135.2,
3
31.9, 67.7, 40.7, 31.5, 30.3, 29.9, 26.1, 24.9 ppm; IR (ATR): ṽmax = 3315, 2933, 2862, 1463,
–
1
450, 1376, 1049, 1029, 1012, 973, 900, 851, 809, 733, 702 cm ; HRMS (EI): m/z for
+
+
C H O [M] : calcd.: 138.1039, found: 138.1048.
9
14
2
3
5
-endo-Mesyloxymethylbicyclo[2.2.2]oct-2-ene (S7). To a solution of bicyclic alcohol S6
(
14.4 g, 104 mmol, 1.00 eq.) in pyridine (26.0 mL) at 0 °C was added dropwise MsCl
8.85 mL, 13.1 g, 114 mmol, 1.10 eq.). The resulting reaction mixture was allowed to warm to
(
room temperature and allowed to stand at this temperature for 4 h after which time H O
2
(
6 mL) was added. The reaction mixture was poured into H O (50 mL) and extracted with
2
Et O (3 x 75 mL). The combined organic layer was washed with 1 m HCl (100 mL), H O
2
2
(
100 mL), brine (100 mL), dried (Na SO ) and concentrated in vacuo. Purification of the
2 4
residue by flash column chromatography (silica, hexanes : EtOAc = 9 : 1) afforded mesylate
S7 (21.4 g, 95%) as a colorless oil.
1
R = 0.19 (hexanes : EtOAc = 9 : 1); H NMR (600 MHz, CDCl ): δ = 6.33 – 6.29 (m, 1H),
f
3
6
1
.14 – 6.10 (m, 1H), 3.81 – 3.79 (m, 2H), 2.98 (s, 3H), 2.65 – 2.61 (m, 1H), 2.55 – 2.51 (m,
H), 2.18 – 2.11 (m, 1H), 1.72 (ddd, J = 12.6, 9.7, 2.7 Hz, 1H), 1.55 – 1.47 (m, 2H), 1.33 –
13
1.25 (m, 2H), 0.74 (dddd, J = 12.8, 5.3, 3.1, 3.1 Hz, 1H) ppm; C NMR (150 MHz, CDCl ):
3
δ = 135.6, 131.2, 73.6, 37.4, 37.4, 31.0, 29.6, 29.6, 25.4, 24.6 ppm; IR (ATR): ṽmax = 2940,
–1
+
2
866, 1351, 1172, 981, 946, 904, 868, 840, 814, 706 cm ; HRMS (EI): m/z for C H O S
10 16 3
+
[
M] : calcd.: 216.0815, found: 216.0814.
2
3
5
-endo-Cyanomethylbicyclo[2.2.2]oct-2-ene (S8).
Mesylate S7 (22.5 g, 104 mmol,
1
.00 eq.) was dissolved in DMF (46.0 mL) and NaCN (11.3 g, 231 mmol, 2.22 eq.) and NaI
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(0.363 g, 2.42 mmol, 0.023 eq.) were added and the mixture was heated to 110 °C for 16 h.
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8
9
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The reaction mixture was allowed to cool to room temperature and was then poured into H O
2
(100 mL). The aqueous layer was extracted with hexanes (3 x 100 mL). The combined
organic layer was washed with H O (150 mL), brine (150 mL), dried (Na SO ) and
2
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
concentrated in vacuo. Purification of the residue by flash column chromatography (silica,
hexanes : Et O = 9 : 1 to 4 : 1) afforded nitrile S8 (10.3 g, 67%) as a colorless oil.
2
1
R = 0.41 (hexanes : EtOAc = 9 : 1); H NMR (600 MHz, CDCl ): δ = 6.33 (ddd,
f
3
J = 8.0, 6.7, 1.0 Hz, 1H), 6.14 – 6.10 (m, 1H), 2.59 – 2.56 (m, 1H), 2.56 – 2.52 (m, 1H), 2.12
2.04 (m, 3H), 1.88 – 1.83 (m, 1H), 1.54 (dddd, J = 12.1, 9.8, 4.0, 2.5 Hz, 1H), 1.45 (dddd,
J = 12.0, 9.8, 4.2, 2.3 Hz, 1H), 1.34 (dddd, J = 12.1, 12.0, 4.2, 3.4 Hz, 1H), 1.22 (ddddd,
–
1
3
J = 12.0, 12.0, 4.0, 3.1, 3.1 Hz, 1H), 0.86 – 0.81 (m, 1H) ppm; C NMR (150 MHz, CDCl ):
3
δ = 135.9, 130.7, 119.6, 34.9, 34.0, 33.3, 29.9, 25.7, 24.5, 24.1 ppm; IR (ATR): ṽmax = 2937,
–
1
+
+
2
1
5
866, 1425, 1376, 707 cm ; HRMS (EI): m/z for C H N [M] : calcd.: 147.1043, found:
1
0
13
47.1034.
2
3
-endo-Carboxymethylbicyclo[2.2.2]oct-2-ene (S9). A mixture of nitrile S8 (10.3 g,
69.7 mmol, 1.00 eq.) and KOH (7.82 g, 139 mmol, 2.00 eq.) in ethylene glycol (40.0 mL) was
heated to 155 °C and stirred at this temperature for 2 h. The reaction mixture was allowed to
cool to room temperature, was diluted with H O (100 mL) and extracted with Et O (100 mL).
2
2
The aqueous layer was acidified (1 m HCl) and extracted with Et O (8 x 100 mL). The
2
combined organic layer was washed with H O (200 mL), brine (200 mL), dried (Na SO ) and
2
2
4
concentrated in vacuo to afford bicyclic acid S9 (11.0 g, 95%) as a colorless solid.
1
R = 0.16 (hexanes : EtOAc = 9 : 1); mp 39  41 °C; H NMR (600 MHz, CDCl ): δ = 6.31 –
f
3
6
.27 (m, 1H), 6.14 – 6.10 (m, 1H), 2.50 – 2.46 (m, 1H), 2.45 – 2.42 (m, 1H), 2.21 (dd,
J = 14.4, 7.0 Hz, 1H), 2.18 – 2.12 (m, 1H), 2.07 (dd, J = 14.4, 7.3 Hz, 1H), 1.83 (ddd,
J = 12.5, 9.2, 2.7 Hz, 1H), 1.55 (dddd, J = 12.3, 9.8, 3.9, 2.6 Hz, 1H), 1.45 (dddd,
J = 11.8, 9.8, 4.1, 2.3 Hz, 1H), 1.28 (dddd, J = 12.3, 12.1, 4.1, 3.3 Hz, 1H), 1.20 (ddddd,
J = 12.1, 11.8, 3.9, 3.1, 3.0 Hz, 1H), 0.84 (dddd, J = 12.5, 4.7, 3.0, 3.0 Hz, 1H) ppm;
13
C NMR (150 MHz, CDCl ): δ = 179.6, 135.3, 131.6, 41.9, 34.4, 34.3, 33.8, 30.0, 26.1, 24.3
3
–
1
ppm; IR (ATR): ṽmax = 3042, 2935, 1702, 1408, 1294, 1230, 938, 706 cm ; HRMS (EI): m/z
+
+
for C H O [M] : calcd.: 166.0988, found: 166.0990.
1
0
14
2
23
Iodolactonization of Carboxylic Acid S9. Carboxylic acid S9 (16.1 g, 97.0 mmol,
.00 eq.) was suspended in H O (47.0 mL) and dissolved by dropwise addition of cold 50 wt-
1
2
%
aqueous NaOH. Solid NaHCO was added to saturation and a solution of I (40.9 g,
3 2
1
61 mmol, 1.66 eq.) and KI (37.5 g, 226 mmol, 2.33 eq.) in H O (125 mL) was added. The
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resulting mixture was stirred at room temperature for 2 h and then decolorized by addition of
solid Na S O . The layers were separated and the aqueous layer was extracted with EtOAc (3
2
2
3
x 600 mL). The combined organic layer was washed with 1 n NaOH (450 mL), brine
(
450 mL), dried (Na SO ) and concentrated in vacuo. The desired iodolactone 29 (25.9 g,
2 4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
1%) was obtained as a colorless solid by recrystallization from EtOAc. Purification of the
residue after four recrystallizations by flash column chromatography (silica, hexanes : EtOAc
= 9 : 1 to 4 : 1) afforded rearranged iodolactone S10 122 mg, 0.4%) as a colorless solid.
Crystals suitable for single crystal X-ray diffraction could be obtained by recrystallization
from EtOAc for both compounds.
5
,10
6
-Iodo-4-oxatricyclo[7.1.1.0 ]undecan-3-one (S10)
1
R = 0.44 (hexanes : EtOAc = 3 : 1); mp 94 – 97°C; H NMR (600 MHz, CDCl ): δ = 4.79
f
3
(dd, J = 5.6, 3.3 Hz, 1H), 4.56 (ddd, J = 3.3, 3.3, 3.3 Hz, 1H), 2.97 – 2.87 (m, 2H), 2.60 –
2
1
1
.52 (m, 1H), 2.48 (dd, J = 16.8, 2.5 Hz, 1H), 2.38 (dd, J = 16.8, 4.0 Hz, 1H), 2.10 – 2.05 (m,
H), 2.02 (dddd, J = 15.3, 12.4, 4.7, 3.3 Hz, 1H), 1.85 (dddd, J = 14.6, 12.4, 6.9, 5.1 Hz, 1H),
1
3
.74 – 1.67 (m, 1H), 1.62 – 1.55 (m, 1H), 1.45 – 1.39 (m, 1H) ppm; C NMR (150 MHz,
CDCl ): δ = 171.5, 78.2, 32.9, 30.2, 30.0, 28.2, 27.7, 27.1, 23.0, 22.4 ppm; IR (ATR): ṽmax
=
3
–
1
2
927, 1735, 1361, 1236, 1228, 1215, 1174, 1146, 1066, 1037, 973 cm ; HRMS (EI): m/z for
+
+
C H IO [M] : calcd.: 291.9955, found: 291.9956.
10
13
2
3
,8
2
-Iodo-4-oxatricyclo[5.3.1.0 ]undecan-5-one (29)
1
R = 0.39 (hexanes : EtOAc = 3 : 1); mp 125  127 °C; H NMR (600 MHz, CDCl ): δ = 5.03
f
3
– 5.00 (m, 1H), 4.32 – 4.27 (m, 1H), 2.58 (dd, J = 18.2, 5.4 Hz, 1H), 2.48 (dd,
J = 18.2, 1.9 Hz, 1H), 2.20 (ddd, J = 14.1, 11.1, 3.7 Hz, 1H), 2.15 – 2.08 (m, 1H), 2.01 – 1.93
(m, 2H), 1.89 – 1.84 (m, 1H), 1.82 – 1.74 (m, 2H), 1.54 – 1.45 (m, 1H), 1.39 (dddd,
13
J = 14.1, 5.1, 2.8, 2.8 Hz, 1H) ppm; C NMR (150 MHz, CDCl ): δ = 168.9, 87.1, 39.3, 33.7,
3
33.2, 32.3, 29.8, 24.5, 21.4, 20.0 ppm; IR (ATR): ṽmax = 2943, 1718, 1381, 1370, 1353, 1225,
–
1
+
+
1
210, 1179, 1143, 1094, 1056, 1032, 1004, 836 cm ; HRMS (EI): m/z for C H IO [M] :
10 13 2
calcd.: 291.9955, found: 291.9940.
2
-endo-Hydroxy-6-endo-(2-hydroxyethyl)-bicyclo[2.2.2]octane (30). A suspension of
LiAlH (9.96 g, 263 mmol, 5.00 eq.) in THF (400 mL) was heated to 66 °C and a solution of
4
iodolactone 29 (15.3 g, 52.5 mmol, 1.00 eq.) in THF (100 mL) was added over the course of
1
.5 h. After complete addition the reaction mixture was refluxed for an additional 6 h and was
then cooled to 0 °C. Rochelle salt was added to provide a homogeneous solution. The reaction
mixture was extracted with EtOAc (3 x 400 mL). The combined organic layer was washed
with brine (350 mL), dried (Na SO ) and concentrated in vacuo. Purification of the residue by
2
4
28
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Page 29 of 39
The Journal of Organic Chemistry
1
2
3
4
5
flash column chromatography (silica, hexanes : EtOAc = 1 : 1) afforded desired diol 30
(
8.26 g, 92%) as a colorless solid. Recrystallization of diol 30 from CH Cl afforded crystals
2 2
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
suitable for single crystal X-ray diffraction.
R = 0.21 (hexanes : EtOAc = 1 : 1); mp 81  83 °C; H NMR (600 MHz, CDCl ): δ = 4.02
1
f
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
dddd, J = 9.8, 3.5, 3.5, 1.4 Hz, 1H), 3.73 (ddd, J = 10.8, 5.5, 5.5 Hz, 1H), 3.64 (ddd,
J = 10.8, 8.1, 5.2 Hz, 1H), 2.39 (br s, 2H), 1.98 (dddd, J = 13.2, 9.8, 3.0, 2.5 Hz, 1H), 1.92
dddd, J = 13.8, 8.1, 8.0, 5.5 Hz, 1H), 1.86 – 1.78 (m, 3H), 1.78 – 1.72 (m, 1H), 1.72 – 1.68
(m, 1H), (m, 1H), 1.46 – 1.37 (m, 3H), 1.37 – 1.30 (m, 1H), 1.24 (dddd,
(
13
J = 12.2, 5.9, 2.5, 2.5 Hz, 1H) ppm; C NMR (150 MHz, CDCl ): δ = 71.3, 62.2, 40.6, 38.2,
3
3
1
4.9, 34.7, 33.1, 25.9, 25.5, 23.6 ppm; IR (ATR): ṽmax = 3324, 2925, 2861, 1453, 1378, 1331,
–
1
163, 1102, 1078, 1035, 1002, 948, 928, 874, 846, 752 cm ; HRMS (ESI–): m/z for
–
4
– –
C H O [M+HCO ] : calcd.: 215.1289, found: 215.1289.
11
19
2
2
-(2-oxobicyclo[2.2.2]octan-6-endo-yl)acetaldehyde (31). A solution of DMSO (2.30 mL,
2
.53 g, 32.4 mmol, 5.40 eq.) in CH Cl (16.6 mL) was added dropwise to a solution of oxalyl
2
2
chloride (7.80 mL, 2 m in CH Cl , 10.4 g, 15.6 mmol, 2.60 eq.) in CH Cl (58.0 mL) at
2
2
2
2
–78 °C. The internal temperature was monitored during the addition to insure that the
temperature did not rise above –50 °C. At 78 °C a solution of diol 30 (1.02 g, 6.00 mmol,
1
.00 eq.) in CH Cl (20.0 mL) was added dropwise to the dimethylchlorosulfonium chloride
2 2
solution and after complete addition the mixture was stirred for an additional 1 h at 78 °C.
During the addition of the alcohol precipitation of a white solid was observed to afford an
opaque solution. Triethylamine (8.34 mL, 60.0 mmol, 10.0 eq.) was added in one portion and
the reaction was stirred for 10 min at –78 °C during which time the precipitate dissolved
again to afford a clear solution. The solution was slowly (30 min) warmed to 0 °C and
maintained at 0 °C for 1 h. Upon warming a white solid again precipitated. The cold solution
was partitioned between saturated aqueous NaHCO (100 mL) and CH Cl (50 mL). The
3
2
2
layers were separated, and the aqueous layer was extracted with CH Cl (3 x 100 mL). The
2
2
combined organic layer was washed with brine (100 mL), dried (Na SO ) and concentrated in
2
4
vacuo. The crude reaction products (0.95 g, 95%) were used without further purification in
the next step.
1
R = 0.51 (hexanes : EtOAc = 1 : 1); H NMR (600 MHz, CDCl ): δ = 9.72 – 9.70 (dd,
f
3
J = 1.5, 1.3 Hz, 1H), 2.54 (ddddd, J = 10.4, 8.3, 6.2, 6.1, 2.3 Hz, 1H), 2.45 (ddd,
J = 17.7, 6.2, 1.3 Hz, 1H), 2.30 (ddd, J = 17.7, 8.3, 1.5 Hz, 1H), 2.27 – 2.22 (m, 1H), 2.20 –
2
.07 (m, 4H), 1.93 – 1.85 (m, 1H), 1.81 (dddd, J = 14.0, 11.3, 5.7, 2.8 Hz, 1H), 1.72 – 1.59
13
(
m, 2H), 1.08 (dddd, J = 11.4, 5.8, 2.6, 2.8 Hz, 1H) ppm; C NMR (150 MHz, CDCl ): δ =
3
29
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