Formation of polycyclic lactones through a ruthenium-catalyzed ring-closing metathesis/hetero-pauson-khand reaction sequence

Article abstract of DOI:10.1021/jo200359c

Processes that form multiple carbon-carbon bonds in one operation can generate molecular complexity quickly and therefore be used to shorten syntheses of desirable molecules. We selected the hetero-Pauson-Khand (HPK) cycloaddition and ring-closing metathe

Full text of DOI:10.1021/jo200359c

FEATURED ARTICLE
pubs.acs.org/joc
Formation of Polycyclic Lactones through a Ruthenium-Catalyzed
Ring-Closing Metathesis/Hetero-PausonꢀKhand Reaction Sequence
David F. Finnegan and Marc L. Snapper*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S Supporting Information
b
ABSTRACT: Processes that form multiple carbonꢀcarbon bonds in one
operation can generate molecular complexity quickly and therefore be
used to shorten syntheses of desirable molecules. We selected the hetero-
PausonꢀKhand (HPK) cycloaddition and ring-closing metathesis
(RCM) as two unique carbonꢀcarbon bond-forming reactions that could
be united in a tandem ruthenium-catalyzed process. In doing so, complex
polycyclic products can be obtained in one reaction vessel from acyclic
precursors using a single ruthenium additive that can catalyze sequentially two mechanistically distinct transformations.
’ INTRODUCTION
chelating group adjacent to the carbonyl functionality in their
cycloadditions.
Tandem catalysis is a process in which a substrate is trans-
formed by two or more mechanistically distinct transformations in
a single reaction vessel with all the catalysts present at the outset.1
Since two steps are replaced with one, this strategy allows for the
controlled generation of molecular complexity with a significant
reduction of energy, waste stream, time, materials, and overhead
costs. While there are several examples of ruthenium-catalyzed
tandem processes involving olefin metathesis2 followed either by
hydrogenation,3 isomerization,4 or oxidation,5 there are relatively
few cases in which the subsequent metal-catalyzed reactions create
additional carbonꢀcarbon bonds. Representative examples include
a tandem ring-closing metathesis/Kharasch addition,6 an enyne
metathesis/cyclopropanation,7 an enyne; RCM/hydrovinylation,8
and a cross-metathesis/hydroarylation sequence.9 Each of these
tandem processes generate new carbonꢀcarbon bonds through two
or more unique ruthenium-catalyzed mechanisms in a single
reaction vessel. Considering the importance of streamlining synth-
eses toward complex molecular targets, we report herein a new
tandem process that combines a ruthenium-catalyzed ring-closing
metathesis (RCM) with a ruthenium-catalyzed [2 þ 2þ1] hetero-
PausonꢀKhand (HPK) cycloaddition.10
’ RESULTS AND DISCUSSION
To develop the tandem olefin metathesis/HPK reaction
sequence, the nature of the ruthenium in the two transformations
is of importance. Specifically, differences in oxidation state and
associated ligands about the ruthenium catalyst in the metathesis
and HPK steps need to be considered. Our plan was to modify
the reactivity of one of Grubbs' metathesis catalysts (3ꢀ5)
through the addition of reductants and CO to convert the
ruthenium species into a HPK catalyst. We selected Murai’s
HPK cycloaddition between di-2-pyridyl ketone (1) and cyclo-
pentene (eq 1 and Scheme 1) to screen for the additives
necessary to convert the olefin metathesis catalyst into a HPK
active species. Considering the potential challenges of carrying
out the metathesis in the presence of pyridine-containing
substrates,15 we focused our catalyst screening attention on the
less costly but more thermally robust Grubbs' second-generation
catalyst 4.
The hetero-PausonꢀKhand reaction is a powerful strategy for
generating functionalized polycyclic γ-lactones and γ-lactams.
The earliest examples of hetero-PausonꢀKhand (HPK) reac-
tions came from the Crowe11 and Buchwald12 laboratories.
These reports featured a titanium-mediated cycloaddition; how-
ever, more recent HPK reactions have been demonstrated using a
wide variety of metal complexes as catalysts.13
The Murai group, in particular, explored the scope of the
ruthenium-catalyzed HPK reaction.14 Inter- and intramolecular
examples of this ruthenium-catalyzed transformation are illu-
strated in eqs 1 and 2. In addition to outlining variables regarding
the catalyst, the Murai team noted the importance of providing a
Received: February 23, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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FEATURED ARTICLE
Scheme 1. Conversion of Grubbs' Olefin Metathesis
Catalysts into Hetero-PausonꢀKhand Active Complexes
Substrate Preparation. To prepare substrates for the tan-
dem RCM/HPK reaction sequence, we started from the commer-
cially available dienol 7, which was used to make iodide 9
(Scheme2).6a Dienol 7is treated under Johnson ortho-ester Claisen
rearrangement conditions to yield ester 8. The ester 8 is then
reduced with LAH to give an alcohol, which is converted to iodide 9
using I2 and PPh3. Several tandem RCM/cycloaddition substrates
could then be prepared from this common intermediate. For
example, when iodide 9 is metalated using t-BuLi and added to
the appropriate Weinreb amide,18 the desired diene 10 is afforded in
an unoptimized yield of 63%. With diene 10 in hand, the ruthenium-
catalyzed intramolecular tandem RCM/HPK sequence could be
explored.
The presence of Lewis basic functionalities, such as a
pyridine group in substrate 10, can cause problems in the
metathesis step.19 Coordination of the pyridine nitrogen to
the ruthenium catalyst can block a necessary coordination site
on the metal and inhibit metathesis activity.20 In the case of
the pyridyl ketone 10, we found that the RCM step would
proceed efficiently by heating the reaction mixture with
Grubbs' second-generation catalyst 4 in toluene to 100 °C.
Under these conditions, the desired RCM product 15 can be
isolated in 92% yield (Scheme 3). The success of the metath-
esis step in the presence of the ketopyridine functionality
bodes well for developing the tandem process. After consider-
able optimization, we found that when substrate 10 is heated
with 10 mol % of catalyst 4, then allowed to cool, reacted with
Scheme 2. Six-Membered Ring Metathesis Substratesa
Scheme 3. Ru-Catalyzed Tandem RCM/HPK Cyclization of
Diene 10
a Conditions: (a) CH3C(OEt)3, CH3CH2CO2H, reflux (88% yield); (b)
LAH (99% yield); (c) I2, PPh3 (65% yield); (d) t-BuLi, Et2O, ꢀ78 °C;
N-methoxy-N-methylpicolinamide; (61% yield); (e) t-BuLi, ꢀ78 °C,
Et2O; N-methoxy-N-methylbenzamide (26% yield); (f) Mg0; pyrimidine-
2-carbonitrile; (45% yield); (g) t-BuLi, ꢀ78 °C, Et2O; 1,3,5-trioxane
(47% yield). (h) PPh3, I2 (66% yield); (i) t-BuLi, ꢀ78 °C, Et2O; N-
methoxy-N-methylpicolinamide (57% yield).
CO and NaOMe, and then reheated under a CO atmosphere,
tricyclic compound 16 is produced from diene 10 as a single
diastereomer (Scheme 3 and Table 1, entry 1) in a 72% yield
for the tandem process.
Ruthenium complex 4 was first treated with CO to form
Diver’s complex 6 in situ.16 That species was then subjected to
reducing agents such as Zn0, Li0, CaH, NaH, NaBH4,
NaBH3CN, and H2. These additives gave no HPK activity
except for NaH. While encouraging, this additive proved
unreliable. Further screening of basic additives such as NaOH,
KOH, and NaOMe showed NaOMe to give consistent
results.17 In this case, reproducible yields of cycloadduct 2
were obtained using 10 mol % of catalyst 4, 10 mol % of
NaOMe, and approximately 5 atm of CO. After optimization
of catalyst and NaOMe loading, CO pressure, and reaction
times, the yield of the HPK was increased to 73%. These
optimized conditions provide a suitable starting point for
development of the tandem RCM/HPK reaction sequence.
To test the role of the pyridine functionality in the tandem
process, phenyl ketone 14 was prepared (Scheme 2). Iodide 9
was metalated with t-BuLi and then reacted with a Weinreb
amide to provide phenyl ketone 14. As shown in eq 3, this
phenyl ketone substrate 14, along with 1 equiv of diene 10,
was then subjected to the optimized tandem RCM/HPK
conditions. The resulting reaction mixture consisted of the
tricyclic HPK product 16 (65% yield) derived from the pyridyl
ketone substrate 10, along with the ring-closed product 17
(80% yield) produced from phenyl ketone 14. No HPK
product derived from phenyl ketone 14 was observed. This
indicates that the pyridyl ketone functionality does not serve
in an intermolecular sense as a ligand that modifies the overall
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Table 1. RCM/Cycloaddition Results
Scheme 4. Synthesis of Substrate 21a
a Conditions: (a) isopropyl Grignard; CuCN 2LiCl, (E)-8-bromoocta-
3
1,6-diene (1.2:1 SN20:SN2, 44% yield of 32); (b) 2-bromopyridine,
n-BuLi (64% yield).
Figure 1. Crystal structure of 22.
The effects of a longer tether length on the HPK were next
examined. Again, access to the desired substrate 13 was realized
from intermediate 9. As summarized in Scheme 2, iodide 9 was
homologated to iodide 12 by treatment with t-BuLi and addition
of the resulting lithiated compound to 1,3,5-trioxane to generate
the homologated alcohol. The alcohol was then converted to
iodide 12 by treatment with I2 and PPh3. Iodide 12 was then
reacted with t-BuLi and the appropriate Weinreb amide to form
pyridyl ketone 13. When substrate 13 was submitted to the
optimized RCM/HPK conditions, the product mixture consisted
mainly of the RCM product with possible trace amounts of the
desired cycloadduct 20. These results suggest that this substrate
may be slower to undergo the HPK cycloaddition than the
shorter tethered analogues.14e
a Conditions: (a) 4 (10 mol %), 100 °C, toluene; NaOMe (20 mol %),
CO (7 atm), 180 °C, 36 h; (b) 24 h cycloaddition.
reactivity of the HPK catalyst but appears to be a necessary
component of the substrate in the intramolecular HPK
cycloaddition step.
To investigate additional parameters and expand the scope of
the tandem process, several other substrates were synthesized.
For example, the role of the ketone and its tether in the HPK
step was examined through the preparation of a substrate with
an aromatic, conformationally restricted, nonenolizable ketone
21. As shown in Scheme 4, substrate 21 was prepared by
allylation of iodide 3121 to give a slight preference for the
branched Weinreb amide 32, along with considerable amounts
of the undesired linear substrate. Treatment of Weinreb amide
32 with 2-lithiopyridine resulted in the formation of pyridyl
ketone 21.
When diene 21 was subjected to the tandem RCM/HPK
conditions, tetracyclic compound 22 was generated in 61% yield
(Table 1, entry 5). The slight decrease in yield compared to the
formation of 16 may be due to the additional rigidity of this
aromatic system. In any case, spectroscopic studies on this
product indicated that the relative stereochemical outcome of
this cycloaddition proceeded to that of cycloadduct 16.22 As
shown in Figure 1, a crystal structure was obtained to aid in the
To further explore the role of the pyridine functionality in the
tandem process, the less basic pyrimidine variant 11 was pre-
pared. The pyrimidine substrate was also accessed from iodide 9
through Grignard formation and addition to pyrimidine-2-car-
bonitrile. When the resulting pyrimidyl ketone 11 was submitted
to the RCM/HPK conditions only the RCM product was
observed (Table 1, entry 3). Apparently, the cycloaddition step
is sensitive to the Lewis basicity of the chelating functionality
adjacent to the carbonyl group. Additional studies are necessary
to better understand the electronic and steric variability allowed
in this region of the substrate.
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Scheme 5. Syntheses of Five- and Seven-Membered
Ring-Containing Substrates 23 and 25a
Scheme 6. Synthesis of Substrates 27 and 29a
a Conditions: (a) HN(Me)OMe HCl, AlMe3 (57% yield); (b) NaH,
3
a Conditions: (a) I2, PPh3 (76% yield); (b) t-BuLi, Et2O, ꢀ78 °C;
N-methoxy-N-methylpicolinamide (38% yield); (c) vinylmagnesium
chloride, CuI, TMSCl (76% yield); (d) LAH (89% yield); (e) I2,
PPh3 (75% yield); (f) t-BuLi, Et2O, ꢀ78 °C; N-methoxy-N-methylpi-
colinamide (55% yield).
allyl bromide (54% yield); (c) n-BuLi, 2-bromopyridine (53% yield);
(d) CH3C(OEt)3, CH3CH2CO2H (75% yield); (e) LAH, Et2O (52%
yield); (f) I2, PPh3 (50% yield); (g) t-BuLi; N-methoxy-N-methylpico-
linamide (38% yield).
and single-crystal X-ray diffraction studies indicated a difference in the
stereochemical outcome for the intramolecular cycloaddition of the
seven-membered ring-containing substrate (Figure 2). The five- and
six-membered rings 16 and 24 resulted in the bridgehead protons
having a syn-stereochemical relationship; however, increasing the size
of the metathesis ring resulted in an inversion of the relative
stereochemistry of the bridgehead carbon.
The relative stereochemistry of these ring systems is estab-
lished in the HPK reaction. In as much as the intermediate
ruthenacycles in the HPK cycloadditions resemble the products,
we determined the relative energies of these cycloadducts and
their corresponding diastereomers through MM2 and DFT
calculations (Figure 2). In both the six- and seven-membered
ring examples, the lower energy diastereomers are the products
observed.
The ruthenium-catalyzed HPK work described by Murai
indicates that olefin isomerization can, at times, lead to undesired
side products.14 To test whether this would be an issue with our
tandem process, we prepared and tested substrates in which an
allylic ether linkage is present in the ring generated through
RCM. As shown in Scheme 6, access to these systems is possible
from the known lactone 34.25 Conversion of 34 to Weinreb
amide 35 and allylation of the resulting free alcohol by treatment
with NaH and allyl bromide generated diene 36. This diene was
then treated with lithiated 2-bromopyridine to provide the
desired pyridyl ketone 27.
Submission of pyridyl ketone 27 to the tandem RCM/HPK
conditions resulted in the formation of tricyclic lactone 28 in 51%
yield (Table 1, entry 8). Analysis of the crude 1H NMR spectrum
suggested that the primary side product is the isomerized
disubstituted enol ether with the olefin conjugated to the ether
linkage.26 The side product was not stable to our purification
conditions.
To check whether the isomerization side path is affected by
metathesis ring size, a six-membered ether tethered ring was also
synthesized (Scheme 6). Access to this ring-size variant started
by treating the known alcohol 3727 under the Johnson ortho-
ester Claisen rearrangement conditions to form ethyl ester 38 in
75% yield. The ester was then reduced with LiAlH4 to form an
alcohol in 52% yield. Conversion of the alcohol to the iodide
resulted in the formation of 39 in 50% yield. Lithiation of
that iodide with t-BuLi and addition of the Weinreb amide of
Figure 2. Crystal structures and relative energy differences (MM2) for
stereoisomers of cycloadducts 26 and 16.
analysis of this system. The sole diastereomer formed possesses a
cis-relationship between all of the ring junctions and the pyridyl
ring functionality.
As shown in Scheme 5, the precursor to the five-membered ring
variant 23 was synthesized from known alcohol 31a23 by converting
it to iodide followed by treatment with t-BuLi and addition to
N-methoxy-N-methylpicolinamide. Submission of substrate 23 to
the same conditions as 10 resulted in the formation of the tricyclic
lactone 24 in 76% yield (Table 1, entry 6).
With the success of both the five- and six-membered metathesis
ring products, the synthesis of the seven-membered ring variant 25
became of interest. Production of 25 was accomplished through the
pathway also outlined in Scheme 5. Enone 32a was treated with
vinyl Grignard in the presence of CuI resulting in a 1,4-addition.24
The resulting ester 33 was reduced with LiAlH4 to form an alcohol,
which in turn was iodinated using I2 and PPh3. Metalation of the
resulting iodide with t-BuLi and addition to the appropriate Weinreb
amide provided pyridyl ketone 25.
Submission of pyridyl ketone 25 to the tandem RCM/
cycloaddition conditions resulted in the formation of tricyclic
lactone 26 in 71% yield (Table 1, entry 7). NMR spectroscopy
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2-pyridyl carboxylate provided pyridyl ketone 29 in an unopti-
mized 38% yield.
to yield the crude product. The crude reaction mixture was purified by
silica gel chromatography.
Submission of pyridyl ketone 29 to tandem HPK conditions
resulted in the formation of tricyclic structure 30 in 44% yield
(Table 1, entry 9). Once again the primary side product seems to
be the enol ether. The lower yield as compared to five-membered
ring 27 is perhaps due to a more facile olefin isomerization.
General Procedure for Addition of 2-Pyridyl Bromide to a
Weinreb Amide. To a stirring solution of 2-pyridyl bromide in diethyl
ether at ꢀ78 °C was added n-butyllithium. The reaction mixture was
stirred at ꢀ78 °C for 1 h. After that time, the reaction mixture was
transferred by cannula to a reaction flask containing a stirring solution of
Weinreb amide and Et2O (0.05 M) at ꢀ78 °C. The reaction was allowed
to warm to room temperature overnight. At that time, the reaction
was quenched with ammonium chloride (satd) and was extracted
with Et2O brine. The organic layer was dried over MgSO4 and
concentrated to provide the crude product, which was purified by silica
gel chromatography.
1-(Pyridin-2-yl)-4-vinylnon-8-en-1-one (10). To a stirring
solution of the iodine6a 9 (525 mg, 2.00 mmol) in Et2O (8.3 mL) at
ꢀ78 °C was added t-BuLi (2.50 mL, 4.00 mmol, 1.6 M in pentane). After
30 min, a solution of N-methoxy-N-methyl-2-pyridinecarboxamide18
(300 mg, 1.80 mmol) in Et2O (1.5 mL) was added to the reaction
mixture by syringe. The reaction was allowed to stir at ꢀ78 °C for 10 min
and then allowed to warm to room temperature. When the Weinreb
amide had vanished by TLC (∼2 h), the reaction was quenched with
NH4Cl (satd) (5 mL) and extracted with Et2O (3 ꢁ 25 mL) and 2 N
NaOH (3 ꢁ 25 mL). The organic layer was removed, dried over MgSO4,
and concentrated. The crude product was purified by silica gel chroma-
tography (2 cm ꢁ10 cm, 10% Et2O in hexanes) to provide pyridyl
ketone 10 (269 mg 61% yield) as a clear colorless oil. 1H NMR (CDCl3,
400 MHz): δ 1.48ꢀ1.29 (4H, m), 1.65 (1H, ddt J = 13.7, 9.3, 7.3 Hz),
1.84 (1H, dtd, J = 13.6, 7.9, 5.0 Hz), 2.10ꢀ1.98 (3H, m), 3.20 (2H, t, J =
7.3 Hz), 4.93 (1H, ddt, J = 10.0, 2.2, 1.3 Hz), 4.97 (1H, dt, J = 3.8, 1.6 Hz),
4.99 (1H, dd, J = 2.0, 0.6 Hz), 5.02ꢀ5.00 (1H, m), 5.55 (1H, ddd, J =
16.5, 10.8, 8.8 Hz), 5.80 (1H, ddt, J = 17.0, 10.3, 6.8 Hz) 7.45 (1H, ddd, J =
7.5, 4.8, 1.3 Hz), 7.82 (1H, td, J= 7.9, 1.7 Hz), 8.03 (1H, ddd, J= 7.9, 1.3, 0.9
Hz), 8.67 (1H, ddd, J = 4.8, 1.8, 0.9 Hz). 13C NMR (CDCl3, 100 MHz): δ
202.3, 153.8, 149.1, 142.7, 139.1, 136.9, 127.0, 121.9, 115.3, 114.5, 44.0,
35.8, 34.8, 34.0, 29.2, 26.8. FTIR (NaCl, thin film): 3073 (m), 2977 (m),
2860 (m), 1698 (s), 1640 (w), 1584 (w), 1436 (w), 995 (w), 913
(w) cmꢀ1. HRMS (DART, [M þ H]þ): found 244.1711, calcd for
C16H22NO 244.1701.
1-(Pyrimidin-2-yl)-4-vinylnon-8-en-1-one (11). A stock solu-
tion of the Grignard reagent of iodide 9 was prepared by adding a
solution of iodide 9 (1.60 g, 6.00 mmol) and Et2O (3 mL) to a round-
bottom flask containing magnesium turnings (160 mg, 6.60 mmol). The
heterogeneous mixture was refluxed for 5 h at which time the mixture
was cooled and titrated to form a solution of Grignard reagent (0.65 M).
To a 0 °C solution of pyrimidine-2-carbonitrile (85 mg, 0.80 mmol)
in Et2O (1.3 mL) was added the previously formed Grignard reagent
(1.5 mL). The solution was allowed to warm to room temperature
overnight. The reaction was quenched with 2 M HCl (2 mL) and was
treated with NaOH (2 M) until basic. The reaction was then extracted
with Et2O (3 ꢁ 25 mL) and brine (3 ꢁ 25 mL). The organic layer was
dried over MgSO4 and concentrated. The reaction mixture was purified
by silica column chromatography (2 cm ꢁ10 cm, 50% Et2O in hexanes
to 100% Et2O in hexanes) to provide ketone 11 (88.6 mg, 45% yield) as a
clear colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.91 (2H, d, J = 5.0
Hz), 7.44 (1H, t, J = 4.8 Hz), 5.78 (1H, ddt, J = 17.0, 10.3, 6.8 Hz), 5.54
(1H, ddd, J = 16.8, 10.6, 9.0 Hz), 5.02ꢀ4.90 (4H, m), 3.20 (2H, dt, J =
9.0, 6.0 Hz), 2.10ꢀ1.98 (2H, m), 1.89 (1H, dddd, J = 13.4, 9.2, 6.6, 4.6
Hz), 1.73ꢀ1.64 (1H, m), 1.47ꢀ1.30 (5H, m). 13C NMR (CDCl3, 100
MHz): δ 199.9, 160.3, 157.6, 142.4, 138.9, 122.9, 115.3, 114.4, 43.8,
37.1, 34.6, 33.9, 28.9, 26.6. FTIR (NaCl, thin film): 3074 (m), 2976 (m),
2861 (m), 1715 (s), 1640 (w), 1563(s), 1413 (m), 1368 (w), 1324 (w),
998 (m), 914 (m) cmꢀ1. HRMS (DART, [M þ H]þ): found 245.1648,
calcd for C15H21N2O 245.1654.
’ CONCLUSION
We have demonstrated that the popular Grubbs' second-
generation, ruthenium-based, olefin metathesis catalyst 4 can
be converted in situ into a catalyst that affects a hetero-Pau-
sonꢀKhand reaction by treatment with CO followed by reduc-
tion with NaOMe. This advancement has allowed for the
introduction of a tandem metathesis/HPK reaction sequence.
The net result is a process that converts acyclic, carbonyl-
containing dienes into polycyclic, lactone-containing ring sys-
tems with the addition of one ruthenium precatalyst in a single
reaction vessel.
’ EXPERIMENTAL SECTION
General Experimental Methods. Starting materials and reagents
were purchased from commercial suppliers and used without further
purification except as follows: Grubbs' second-generation olefin metath-
esis catalyst 4 was purified by silica gel chromatography (20% Et2O in
hexanes) to isolate the intensely colored band (cranberry red); tetra-
hydrofuran and CH2Cl2 were dried on alumina columns using a solvent
dispensing system;28 hexanes were distilled prior to use in chromatog-
raphy. Dry methanol was prepared by distillation from Mg(OMe)2.
Sodium methoxide solution (0.50 M) was prepared immediately prior to
use by dissolving sodium hydride (12 mg, 0.50 mg) in dry methanol
(1.0 mL). All reactions were conducted in oven- (135 °C) or flame-dried
glassware under an inert atmosphere of dry nitrogen. Carbon monoxide
pressurized reactions were run in a pressure vessel. The silica gel
(230ꢀ400 mesh) used for purification was oven-dried before use.
General Procedure for the Tandem Ring-Closing Metath-
esis/Hetero-PausonꢀKhand Reaction. Inside a nitrogen atmo-
sphere drybox, a magnetic stir bar was placed in an oven-dried glass
pressure vessel and the vessel was capped with a rubber septum. The
edges of the septum were sealed with electrical tape, and the tube was
removed from the drybox and placed under positive N2 pressure. To the
tube was added a mixture of diene (0.15 mmol) and toluene (1.5 mL) by
syringe, followed by a mixture of Grubbs' catalyst 4 (13 mg, 0.015 mmol)
and toluene (1.5 mL). The tube was placed in an oil bath and warmed to
100 °C. After 1 h, heating was discontinued, and the tube was allowed to
cool for 30 min. At that time, CO was sparged into the reaction mixture
for 3 min followed by NaOMe (60 μL, 0.5 M in MeOH, 0.03 mmol) and
a second 3 min sparge of CO. The septum was replaced with a pressure
coupling, and the coupling was attached to a CO tank. The tube was
placed behind a safety shield, and the tube was pressurized to 100 psig
(7 atm) and released three times. On the fourth pressurization the tube
was warmed to 180 °C for 30 h in an oil bath. At the end of that time, the
reaction was allowed to cool to room temperature and the pressure was
released. The solvent was then removed under vacuum to provide the
cycloadduct, which was purified by silica gel chromatography.
General Procedure for Iodination of an Alcohol. Following
the procedure of Seigal et al.,6a iodine was added to a stirring solution of
the alcohol, triphenylphosphine, imidazole, diethyl ether, and acetoni-
trile at 0 °C. After 30 min the reaction was quenched with saturated
sodium thiosulfate (aq). The reaction mixture was extracted with
saturated sodium thiosulfate until the organic phase was colorless.
The organic phase was separated, dried over MgSO4 and concentrated
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1-(Pyridin-2-yl)-5-vinyldec-9-en-1-one (13). To a ꢀ78 °C
stirring solution of the iodide 9 (290 mg, 1.10 mmol) in Et2O (4.0 mL)
was added t-BuLi (1.80 mL, 2.40 mmol, 1.37 M in pentane). The
reaction was stirred for 30 min, at which time the iodide solution was
cannula transferred to a ꢀ78 °C solution of 1,3,5-trioxane (600 mg, 6.70
mmol) in Et2O (2 mL). The reaction was stirred ∼12 h, quenched with
HCl (1.2 M, 1.0 mL), and extracted with Et2O (3 ꢁ 20 mL) and
NaHCO3 (satd) (3 ꢁ 25 mL). The organic layer was dried over MgSO4 and
concentrated. The crude product was purified by silica gel chromatography
(2 cm ꢁ10 cm, 20% Et2O in hexanes) to provide alcohol 9a (79.3 mg, 42%
yield) as a clear colorless oil.
The general iodination procedure was followed with alcohol 9a (87.0
mg, 0.50 mmol), iodine (196 mg, 0.80 mmol), triphenylphosphine (163
mg, 0.60 mmol), imidazole (49 mg, 0.70 mmol), acetonitrile (0.60 mL),
and Et2O (1.0 mL). The reaction mixture was purified by silica gel
chromatography (2 cm ꢁ10 cm, hexanes) to provide iodide 12 (95.3
mg, 66% yield) as a clear colorless oil.
689 (m) cmꢀ1. HRMS (DART, [M þ H]þ): found 243.1753, calcd for
C17H23O 243.1749.
3-(Cyclohex-2-enyl)-1-(pyridin-2-yl)propan-1-one (15). To
a stirring solution of diene 10 (23.7 mg, 0.10 mmol) in toluene (1.0 mL)
was added a solution of catalyst 4 (8.0 mg, 0.010 mmol) in toluene
(1.0 mL). The reaction was warmed to 100 °C for 1 h. The reaction was
then allowed to cool to room temperature and concentrated. The reaction
mixture was purified by silica gel chromatography (1 cm ꢁ 4 cm, 10% Et2O
in hexanes) to provide pyridyl ketone 15 (19.3 mg, 92% yield) as a clear
colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.70ꢀ8.66 (1H, m),
8.06ꢀ8.02 (1H, m), 7.86ꢀ7.80 (1H, m), 7.49ꢀ7.44 (1H, m),
5.73ꢀ5.60 (2H, m), 3.27 (2H, t, J = 7.7 Hz), 2.24ꢀ2.12 (1H, m),
2.02ꢀ1.94 (2H, m), 1.88ꢀ1.68 (4H, m), 1.60ꢀ1.46 (1H, m),
1.34ꢀ1.24 (1H, m). 13C NMR (CDCl3, 100 MHz): δ 202.3, 153.6,
149.0, 136.9, 131.6, 127.5, 127.1, 121.9, 35.3, 35.0, 30.4, 29.1, 25.5, 21.6.
FTIR (NaCl, thin film): 3014 (m), 2947 (m), 2860 (m), 2837 (m), 1696
(s), 1584 (w), 1436 (m), 1369 (m), 1322 (m), 1213 (m), 995 (m), 755
(w), 722 (w), 659 (w), 618 (w) cmꢀ1. HRMS (DART, [M þ H]þ): found
216.1382, calcd for C14H18N1O1 216.1388.
To a solution of the iodine 12 (300 mg, 1.10 mmol) stirring in Et2O
(5.4 mL) at ꢀ78 °C was added t-BuLi (1.7 mL, 2.4 mmol, 1.37 M in
pentane). After 1 h, a solution of 2-pyridyl Weinreb amide18 (358 mg,
2.20 mmol) in Et2O (0.6 mL) was added to the reaction by syringe. The
reaction was allowed to stir at ꢀ78 °C for 10 min and then allowed to
warm to room temperature. When the pyridyl ketone had vanished by
TLC (100% Et2O) (∼2 h), the reaction was quenched with NH4Cl
(satd) (5 mL) and extracted with Et2O (3 ꢁ 25 mL) and brine (3 ꢁ
25 mL). The organic layer was dried over MgSO4 and concentrated. The
product was purified by silica gel chromatography (2 cm ꢁ10 cm, 10%
Et2O in hexanes) to provide pyridyl ketone 13 (158.5 mg 57% yield) as a
clear colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.67 (1H, ddd, J = 4.8,
1.8, 0.9 Hz), 8.03 (1H, dt, J = 7.9, 1.1 Hz), 7.82 (1H, td, J = 7.9, 1.8 Hz),
7.46 (1H, ddd, J = 7.7, 4.8, 1.3 Hz), 5.79 (1H, ddt, J = 16.8, 10.3, 6.6 Hz),
5.59ꢀ5.48 (1H, m), 5.02ꢀ4.90 (4H, m), 3.19 (2H, ddd, J = 8.1, 6.8, 2.2
Hz), 2.1ꢀ1.9 (3H, m), 1.8ꢀ1.6 (2H, m), 1.5ꢀ1.2 (6H, m). 13C NMR
(CDCl3, 100 MHz): δ 202.1, 153.7, 149.0, 143.0, 139.2, 137.0, 127.0,
121.9, 114.6, 114.4, 44.0, 37.9, 34.8, 34.6, 34.0, 26.7, 21.9. FTIR (NaCl,
thin film): 3973 (m), 2976 (m), 2947 (m), 2862 (m), 1698 (s), 1640 (m),
1436 (m), 995 (m), 912 (s) cmꢀ1. HRMS (DART, [M þ H]þ): found
258.1848, calcd for C17H23N1O1 258.1857.
1-Phenyl-4-vinylnon-8-en-1-one (14). To a stirring solution
of t-BuLi (1.74 mL, 1.70 mmol, 0.98 M in pentane) in Et2O (2.0 mL)
at ꢀ78 °C was added a solution of iodine 9 (250 mg, 0.90 mmol) in Et2O
(1.8 mL). After 30 min, a solution of N-benzoyl-N-methyl-O-
methylhydroxylamine29 (149 mg, 0.53 mmol) in Et2O (0.9 mL) was
added to the reaction mixture by syringe. The reaction was allowed to
stir at ꢀ78 °C for 10 min and then allowed to warm to room
temperature. When the N-benzoyl-N-methyl-O-methylhydroxylamine
had vanished as judged by TLC (∼2 h), the reaction was quenched with
NH4Cl (satd) (2 mL) and extracted with Et2O (3 ꢁ 25 mL) and brine
(3 ꢁ 25 mL). The organic layer was dried over MgSO4 and concen-
trated. The crude product was purified by silica gel chromatography
(2 cm ꢁ10 cm, hexanes to 10% Et2O in hexanes) to provide phenyl
ketone 14 contaminated with tert-butyl phenyl ketone. The mixture was
submitted to 10 wt % of AgNO3-impregnated silica gel (2 cm ꢁ10 cm,
50% Et2O in hexanes) to provide phenyl ketone 14 (59.7 mg, 26% yield)
as a clear colorless oil. 1H NMR (CDCl3, 400 MHz): δ 7.98ꢀ7.92 (2H,
m), 7.54 (1H, tt, J = 7.1, 1.3 Hz), 7.45 (2H, t, J = 7.9 Hz), 5.78 (1H, ddt,
J = 16.8, 10.1, 6.8 Hz), 5.54 (1H, ddd, J = 17.2, 10.3, 9.0 Hz), 5.06ꢀ4.90
(4H, m), 2.95 (2H, qdd, J = 17.0, 9.3, 5.7 Hz), 2.10ꢀ1.85 (2H, m), 1.88
(1H, dddd, J = 13.6, 9.0, 6.2, 4.0 Hz), 1.61 (1H, dtd, J = 14.7, 9.2, 5.5 Hz),
1.50ꢀ1.30 (4H, m). 13C NMR (CDCl3, 100 MHz): δ 200.5, 142.5,
139.0, 137.2, 132.9, 128.6, 128.1, 115.4, 114.5, 44.0, 36.5, 34.8, 34.0, 29.3,
26.6. FTIR (NaCl, thin film): 3073 (w), 2976 (w), 2947 (w), 2894 (w),
2860 (w), 1687 (s), 1640 (w), 1580 (w), 998 (m), 912 (m), 740 (w),
(()-(2aR*,2a1S*,5aR*,7aS*)-7a-(Pyridin-2-yl)octahydro-
indeno[1,7-bc]furan-2(2a1H)-one (16). The general tandem
RCM/HPK procedure was followed with diene 10 (37.1 mg, 0.15
mmol). The reaction mixture was purified by silica gel chromatography
(1 cm ꢁ5 cm, 30% Et2O in hexanes with 1% AcOH) to provide lactone
16 (26.6 mg, 72% yield) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ
8.58 (1H, ddd, J = 4.8, 1.5, 0.7 Hz), 7.68 (1H, td, J = 8.1, 1.8 Hz), 7.52
(1H, dt, J = 8.1, 1.1 Hz), 7.20 (1H, ddd, J = 7.7, 4.8, 1.1 Hz), 3.17 (1H, t,
J = 10.3 Hz), 2.78ꢀ2.71 (1H, m), 2.52 (1H, dt, J = 16.5, 9.5 Hz),
2.35ꢀ2.10 (3H, m), 1.80ꢀ1.72 (3H, m), 1.60 (1H, tdd, J = 13.5, 6.2,
3.3 Hz), 1.52ꢀ1.42 (2H, m), 1.38ꢀ1.28 (1H, m). 13C NMR (CDCl3,
100 MHz) δ 179.3, 160.8, 149.3, 136.7, 122.6, 119.5, 96.4, 45.8, 39.8,
37.6, 37.1, 29.7, 26.3, 24.1, 17.5. FTIR (NaCl, thin film): 3059 (w), 3026
(w), 2915 (s), 1771 (s), 1590 (w), 1469 (w), 1436 (w), 1196 (w), 1142
(w), 1050 (w), 958 (w) cmꢀ1. HRMS (DART, Mþ): found 244.1330,
calcd for C15H18N1O2 244.1338. Mp: 120 °C dec.
N-Methoxy-N-methyl-2-(octa-1,7-dien-3-yl)benzamide
(32). To a stirring solution of iodide 3130 (500 mg, 1.70 mmol) and
THF (17 mL) at ꢀ78 °C was added isopropylmagnesium chloride
(1.40 mL, 2.60 mmol, 1.9 M in Et2O). The reaction was allowed to stir
for 1 h at which time a solution of CuCN (310 mg, 3.40 mmol), LiCl
(290 mg, 6.90 mmol), and THF (5 mL) was added by syringe. The
reaction was allowed to stir for 20 min at which time a solution of
8-bromoocta-1,6-diene31 (652 mg, 3.40 mmol) in THF (5 mL) was
added to the reaction mixture, and the reaction was allowed to warm to
room temperature for ∼12 h. The reaction mixture was then filtered
through Celite and extracted with Et2O (3 ꢁ 50 mL) and brine (3 ꢁ
50 mL). The organic layer was dried over MgSO4 and concentrated. The
crude product was purified by silica gel chromatography (2 cm ꢁ10 cm,
50% Et2O in hexanes) to provide a mixture of isomers (386.9 mg, 82%,
SN20:SN2 1.2:1). The isomers were separated on 10 wt % of AgNO3-
impregnated silica gel chromatography (2 cm ꢁ10 cm, 75% EtOAc in
hexanes) to provide diene 32 (208.5 mg, 44% yield) as a clear colorless
1
oil. H NMR (CDCl3, 400 MHz): δ 7.40ꢀ7.20 (4H, m), 5.98ꢀ5.86
(1H, m), 5.82ꢀ5.70 (1H, m), 5.05ꢀ4.90 (4H, m), 4.0ꢀ3.0 (4H, m),
2.04 (2H, q, J = 6.6 Hz), 1.71 (2H, q, J = 6.6 Hz), 1.48ꢀ1.18 (1H, m),
1.34ꢀ1.26 (1H, m). 13C NMR (CDCl3, 100 MHz): δ 141.8, 141.6,
138.8, 135.0, 129.5, 127.1, 126.5, 125.7 (br), 114.5, 61.1, 46.0, 35.1, 33.8,
26.8. FTIR (NaCl, thin film): 3074.0 (m), 2974 (m), 2893 (m), 2860
(m), 1658 (s), 1459.9 (s), 1413.6 (m), 1380 (m), 991 (m), 914 (m),
735 (w) cmꢀ1. HRMS (DART, Mþ): found 274.1805, calcd for
C17H24N1O2 274.1807.
(2-(Octa-1,7-dien-3-yl)phenyl)(pyridin-2-yl)methanone (21).
The general procedure for addition of 2-bromopyridine to a Weinreb
amide was followed by 2-bromopyridine (110.6 mg, 0.70 mmol) and
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n-BuLi (0.20 mL, 0.42 mmol, 2.1 M in hexanes) in Et2O (0.8 mL)
followed by Weinreb amide 32 (95.6 mg, 0.35 mmol) in Et2O (3 mL).
The reaction mixture was purified by silica gel chromatography (2 cm ꢁ
10 cm, 20% Et2O in hexanes to 33% Et2O in hexanes) to provide pyridyl
ketone 21 (64.8 mg, 64% yield). 1H NMR (CDCl3, 400 MHz):
δ 8.71ꢀ8.68 (1H, m), 8.10 (1H, dt, J = 7.9, 1.1 Hz), 7.89 (1H, td, J =
7.7, 1.8 Hz), 7.50ꢀ7.44 (2H, m), 7.40ꢀ7.33 (2H, m), 7.30ꢀ7.24 (1H,m),
5.92(1H, ddd, J=17.4, 10.3, 7.3Hz), 6.69 (1H, ddt, J= 17.0, 10.3, 6.8 Hz),
4.98ꢀ4.84 (4H, m), 3.50 (1H, q, J = 7.5 Hz), 1.94 (2H, q, J = 7.1 Hz), 1.70
(2H, dtd, J = 10.0, 6.8, 4.0 Hz), 1.38ꢀ1.14 (2H, m). 13C NMR (CDCl3,
100 MHz): δ 198.0, 155.0, 149.4, 143.9, 141.6, 138.8, 138.3, 136.9, 130.8,
129.1, 127.5, 126.7, 125.4, 124.2, 114.6, 114.5, 45.3, 35.2, 33.7, 26.8. FTIR
(NaCl, thin film): 3060 (m), 3028 (s), 2934 (m), 2860 (w), 2292 (s),
2225 (s), 1673 (s), 1638 (s), 1580 (m), 1433 (w), 1307 (s), 1242
(w) cmꢀ1. HRMS (DART, [M þ H]þ): found 292.1699, calcd for
C20H22NO1 292.1701.
2.15ꢀ1.95 (3H, m), 1.85 (1H, dtd, J = 13.4, 7.5, 4.2 Hz), 1.67 (1H, ddt, J
= 16.7, 9.3, 7.5 Hz), 1.58ꢀ1.49 (1H, m), 1.40 (1H, dtd, J = 18.7, 9.3, 5.5
Hz). 13C NMR (CDCl3, 100 MHz): δ 202.1, 153.7, 149.0, 142.3, 138.9,
136.9, 127.0, 121.8, 115.5, 114.4, 43.5, 35.7, 34.4, 31.5, 29.0. FTIR
(NaCl, thin film) 3074 (w), 2975 (w), 2942 (w), 2893 (w), 2861 (w),
1697 (s), 1640 (w), 1584 (w), 996 (m), 914 (m) cmꢀ1. HRMS (DART,
[M þ H]þ): found 230.1547, calcd for C15H20NO 230.1545.
(2aS*,2a1S*,4aR*,6aR*)-2a-(Pyridin-2-yl)octahydro-1H-pen-
taleno[1,6-bc]furan-1-one (24). The general tandem RCM/HPK
procedure was followed with diene 23 (30.2 mg, 0.150 mmol). The
reaction mixture was purified by silica gel chromatography (1 cm ꢁ5 cm,
50% Et2O in hexanes with 1% AcOH) to provide lactone 24 (23.0 mg,
76%) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ 8.58 (1H, ddd, J =
4.8, 1.5, 0.9 Hz), 7.68 (1H, td, J = 7.7, 1.8 Hz), 7.53 (1H, dt, J = 7.9, 0.9
Hz), 7.20 (1H, ddd, J = 7.7, 4.9, 0.9 Hz), 3.51 (1H, t, J = 9.5 Hz), 3.08
(1H, td, J = 9.3, 4.0 Hz), 2.94 (1H, pd, J = 8.4, 4.9 Hz), 2.42 (1H, dd, J =
11.0, 7.5 Hz), 2.39 (1H, dd, J = 11.0, 7.3 Hz), 2.34ꢀ2.20 (2H, m),
2.2ꢀ2.08 (2H, m), 1.94 (1H, td, J = 13.4, 7.3 Hz), 1.67ꢀ1.56 (1H, m).
13C NMR (CDCl3, 100 MHz): δ 180.8, 161.8, 149.4, 136.8, 122.5,
119.4, 96.5, 57.7, 47.3, 45.7, 41.8, 32.2, 32.0, 31.2. FTIR (NaCl, thin
film): 3076 (w), 3051 (w), 3016 (w), 1765 (s), 1587 (w), 1468 (w),
(()-(2aR*,2a1S*,5aS*,9bR*)-9b-(Pyridin-2-yl)-2a1,3,4,5,5a,
9b-hexahydrofluoreno[9,1-bc]furan-2(2aH)-one (22). The
general tandem RCM/HPK procedure was followed with diene 21 (44.5
mg, 0.150 mmol). The reaction mixture was purified by silica gel
chromatography (1 cm ꢁ 4 cm, 40% Et2O in hexanes) to provide lactone
22 (27.0 mg, 61% yield) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ
8.56 (1H, ddd, J = 4.8, 1.6, 1.1 Hz), 7.80ꢀ7.72 (2H, m), 7.35 (2H, dqd, J =
14.6, 7.7, 1.1 Hz), 7.25ꢀ7.18 (2H, m), 7.06, (1H, d, J = 7.7 Hz),
3.78 (1H, t, J = 9.5 Hz), 3.68ꢀ3.60 (1H, m), 2.95 (1H, ddd, J = 10.3,
7.7, 2.2 Hz), 2.28ꢀ2.17 (1H, m), 1.95 (1H, dddd, J = 14.0, 8.0, 6.0,
4.0 Hz), 1.90ꢀ1.71(2H, m), 1.60ꢀ1.44 (1H, m), 1.47ꢀ1.36 (1H, m).
13C NMR (CDCl3, 100 MHz): δ 179.6, 160.8, 149.9, 147.9, 142.5, 136.8,
130.0, 127.7, 125.5, 124.3, 122.8, 119.8, 96.9, 46.7, 41.6, 37.2, 28.2, 21.9,
18.7. FTIR (NaCl, thin film): 3060 (w), 3027 (m), 2924 (w), 1767 (s),
1587 (w), 1171 (w), 1125 (m), 751 (s), 697 (s) cmꢀ1. HRMS (DART,
[M þ H]þ): found 292.1335, calcd for C19H18NO2 292.1338. Mp:
110 °C dec.
3-(2-Iodoethyl)hepta-1,6-diene (31b). The general iodination
procedure was followed with alcohol 31a (322.6 mg, 2.30 mmol), iodine
(878 mg, 3.50 mmol), triphenyl phosphine (724 mg, 2.80 mmol), imidazole
(219 mg, 3.20 mmol), acetonitrile (2.8 mL), and Et2O (4.6 mL). The
reaction mixture was purified by silica gel chromatography (2 cm ꢁ10 cm,
hexanes) to provide iodide 31b (428 mg, 76% yield) as a clear, colorless oil.
1H NMR (CDCl3, 400 MHz): δ 5.78 (1H, ddt, J = 16.9, 10.1, 6.6 Hz), 5.44
(1H, dt, J = 18.1, 9.1 Hz), 5.12ꢀ4.92 (4H, m), 3.24 (1H, ddd, J = 9.5, 8.1,
4.9 Hz), 3.06 (1H, dt, J = 9.5, 8.1 Hz), 2.20ꢀ1.87 (4H, m), 1.73 (1H, dddd,
J = 14.3, 9.7, 7.7, 4.9 Hz), 1.51ꢀ1.32 (2H, m). 13C NMR (CDCl3, 100
MHz): δ 140.8, 138.5, 116.5, 114.8, 44.5, 38.6, 33.9, 31.4, 5.1. FTIR (NaCl,
thin film): 3075 (w), 2976 (s), 2936 (w), 2894 (w), 2858 (w), 1640 (s),
1418 (w), 914 (s), 754 (s) cmꢀ1. HRMS (DART, [M þ H]þ): found
251.0304, calcd for C9H16I 251.0297.
1-(Pyridin-2-yl)-4-vinyloct-7-en-1-one (23). To a solution of
iodide 31b (331 mg, 1.30 mmol) stirring in Et2O (4.7 mL) at
ꢀ78 °C was added t-BuLi (1.60 mL, 2.70 mmol, 1.60 M in pentane).
After 1 h, a solution of N-methoxy-N-methyl-2-pyridinecarboxamide18
(300 mg, 1.80 mmol) in Et2O (1.5 mL) was added to the reaction
mixture by syringe. The reaction was allowed to stir at ꢀ78 °C for 10 min
and then allowed to warm to room temperature. When the Weinreb
amide had vanished by TLC (100% Et2O) (∼2 h), the reaction was
quenched with NH4Cl (satd) (5 mL) and extracted with Et2O (3 ꢁ
25 mL) and brine (3 ꢁ 25 mL). The organic layer was removed, dried
over MgSO4, and concentrated. The product was purified by silica gel
chromatography (2 cm ꢁ10 cm, 20% Et2O in hexanes to 50% Et2O in
hexanes) to provide pyridyl ketone 23 (103.9 mg 38% yield) as a clear
colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.69ꢀ8.65 (1H,m),
8.04ꢀ8.00 (1H, m), 7.82 (1H, td, J = 7.9, 1.6 Hz), 7.45 (1H, ddd, J = 7.5,
4.8, 1.3 Hz), 5.80 (1H, ddt, J = 16.9, 10.0, 6.6 Hz), 5.55 (1H, ddd, J =
16.8, 10.3, 9.0 Hz), 5.05ꢀ4.90 (4H, m), 3.20 (2H, t, J = 7.7 Hz),
1434 (w), 1163 (w), 1126 (w), 1001 (w), 751 (w), 696 (w) cmꢀ1
.
HRMS (DART, [M þ H]þ): found 230.1183, calcd for C14H16NO2
230.1181.
Methyl 3-Vinylnon-8-enoate (33). To a solution of CuI (4.60 g,
24.6 mmol) in THF (144 mL) stirring at ꢀ78 °C was added vinylmag-
nesium chloride (10.0 mL, 12.1 mmol, 1.21 M in THF). After 45 min,
TMSCl (9.50 mL, 75.0 mmol) was added in one portion. Then a
solution of ester 32a32 (700 mg, 4.20 mmol) and THF (35 mL) was
added over 30 min. The reaction was stirred at ꢀ78 °C until ester 32 was
gone by TLC (5% Et2O in hexanes). When the reaction was complete, it
was quenched with 1:1 solution of satd NH4OH (aq)/satd NH4Cl (aq)
(25 mL) and extracted with the same 1:1 solution of satd NH4OH (aq)/
satd NH4Cl (aq) with Et2O (3 ꢁ 75 mL) until the aqueous layer was no
longer blue. The organic layer was concentrated and purified by silica gel
chromatography (4 cm ꢁ 10 cm, 5% Et2O in hexanes) to provide diene
33 (718 mg, 88% yield) as a clear colorless oil. 1H NMR (CDCl3, 400
MHz): δ 5.80 (1H, ddt, J = 17.0, 10.3, 6.8 Hz), 5.70 (1H, ddd, J = 17.2,
10.3, 8.4 Hz), 5.05ꢀ4.9 (4H, m), 3.65 (3H, s), 2.56ꢀ2.45 (1H, m), 2.32
(2H, qd, J = 14.7, 6.0 Hz), 2.80ꢀ2.00 (2H, m), 1.44ꢀ1.24 (6H, m). 13C
NMR (CDCl3, 100 MHz): δ 173.0, 141.1, 139,0, 115.1, 114.4, 51.5,
40.5, 40.1, 34.4, 33.8, 28.9, 26.6. FTIR (NaCl, thin film): 3076 (w), 2978
(w), 2949 (m), 2859 (m), 1741 (s), 1641 (w), 1436 (w), 1252 (m), 1164
(m), 994 (m), 914 (m) cmꢀ1. HRMS (DART, [M þ H]þ): found
197.1538, calcd for C12H21O2 197.1542.
3-Vinylnon-8-en-1-ol (33a). To a stirring solution of ester 33
(500 mg, 2.60 mmol) in Et2O (3.2 mL) at ꢀ78 °C was added LAH
(5.10 mL, 5.10 mmol, 1.0 M in Et2O). The reaction was allowed to warm
to room temperature over ∼12 h at which time the reaction was
quenched according to the procedure of Micovic by sequential addition
of 0.2 mL of H2O, 0.2 mL of 15% NaOH, and 0.6 mL of H2O.33 The
white solid was filtered and concentrated under vacuum to provide ester
33a (381.6 mg, 89%) as a clear colorless oil. The crude material was used
without further purification. To provide analytically pure material the
crude material was purified by silica gel chromatography (20% Et2O in
hexanes). H NMR (CDCl3, 400 MHz): δ 5.80 (1H, ddt, J = 16.8, 10.3,
6.6 Hz), 5.56 (1H, dt, J = 18.0, 9.3 Hz), 5.04ꢀ4.90 (4H, m), 3.72ꢀ3.58
(2H, m), 2.16ꢀ1.98 (3H, m), 1.67 (1H, dtd, J = 14.1, 7.3, 4.4 Hz),
1.54ꢀ1.21 (8H, m). 13C NMR (CDCl3, 100 MHz): δ 142.9, 139.1,
114.9, 114.3, 61.3, 41.2, 38.0, 35.2, 33.9, 29.1, 26.7. FTIR (NaCl, thin
film): 3353 (br), 3076 (w), 2977 (w), 2948 (w), 2862 (m), 1640 (m),
1428 (m), 1052 (m), 995 (m), 912 (m) cmꢀ1. HRMS (DART, [M þ
H]þ): found 169.1599, calcd for C11H21O 169.1592.
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3-(2-Iodoethyl)nona-1,8-diene (33b). The general iodination
procedure was followed with alcohol 33a (545.1 mg, 3.20 mmol), iodine
(2.00 g, 8.30 mmol), triphenylphosphine (1.00 g, 3.90 mmol), imidazole
(308 mg, 4.50 mmol), acetonitrile (4.0 mL), and Et2O (6.5 mL). The
reaction mixture was purified by silica gel chromatography (2 cm ꢁ
10 cm, hexanes) to provide iodide 33b (674 mg, 75% yield) as a clear
colorless oil. 1H NMR (CDCl3, 400 MHz): δ 5.80 (1H, ddt, J = 16.9,
10.3, 6.6 Hz), 5.48ꢀ5.38 (1H, m), 5.09ꢀ4.91 (4H, m), 3.24 (1H, ddd,
J = 9.5, 8.1, 5.0 Hz), 3.06 (1H, dt, J = 9.5, 7.9 Hz), 2.14ꢀ2.06 (1H, m),
2.04 (2H, q, J = 7.1 Hz), 1.92 (1H, dtd, J = 14.1, 8.2, 4.4 Hz), 1.72 (1H,
dddd, J = 14.3, 9.5, 7.7, 4.9 Hz), 1.40ꢀ1.24 (6H, m). 13C NMR (CDCl3,
100 MHz): δ 141.2, 139.0, 116.0, 114.4, 45.0, 38.7, 34.6, 33.8, 29.1, 26.6,
5.3. FTIR (NaCl, thin film): 3075 (m), 2976 (m), 2858 (m), 1640 (m),
1418 (m), 1234 (m), 995 (m), 914 (s) cmꢀ1. HRMS (DART, [M þ
H]þ): found 279.0607, calcd for C11H19I 279.0610.
MHz): δ 5.70 (1H, dddd, J = 15.4, 13.0, 6.6, 1.1 Hz), 5.50 (1H, ddd, J =
15.4, 6.6, 1.6 Hz), 4.16ꢀ4.08 (1H, m), 3.68 (3H, s), 3.18 (3H, s),
2.64ꢀ2.47 (2H, m), 1.92ꢀ1.78 (2H, m), 1.72ꢀ1.66 (3H, m). 13C NMR
(CDCl3, 100 MHz): δ 174.9, 133.9, 133.4 (m), 126.5, 126.0 (m), 72.2, 67.0
(m), 61.3, 32.4 (m), 31.9, 31.8 (m), 28.2, 17.8. FTIR (NaCl, thin film):
3421 (b), 2963.1 (s), 2839 (w), 1633 (s), 1463 (m), 1424 (w), 1179 (m),
1125 (w), 1060 (w) cmꢀ1. HRMS (DART, [M þ H]þ): found 188.1283,
calcd for C9H18NO3 188.1287.
(E,Z)-4-(Allyloxy)-N-methoxy-N-methylhept-5-enamide (36).
To a solution of sodium hydride (60 wt %, 32 mg, 0.80 mmol), THF
(1.5mL), andDMF(0.3mL) stirringat0°C was added a solution of alcohol
35 (47.4 mg, 0.30 mmol) and THF (1.5 mL). The reaction was allowed to
stir for 1 h at which time allyl bromide (67 μL, 0.80 mmol) was added in one
portion. The reaction was allowed to warm to room temperature over ∼12 h.
The reaction was quenched with NH4Cl (satd) (1 mL). The reaction was
extracted with Et2O (3 ꢁ 25 mL) and brine (3 ꢁ 25 mL). The organic layer
was dried over MgSO4 and concentrated. The crude product was purified by
silica gel chromatography (1 cm ꢁ10 cm, hexanes to 33% EtOAc in
hexanes) to provide allyl ether 36 (31.3 mg, 54% yield) as a yellow oil. 1H
NMR (CDCl3, 400 MHz): δ 5.86 (1H, dddd, J = 17.2, 16.3, 11.2, 5.9 Hz),
5.63 (1H, tdd, J = 15.4, 6.6, 0.7 Hz), 5.36ꢀ5.28 (1H, m), 5.24 (1H, dq, J =
17.2, 1.7 Hz), 5.13 (1H, dq, J = 10.3, 1.3 Hz), 4.02 (1H, ddt, J = 13.0, 5.3 1.6
Hz), 3.80 (1H, ddt, J = 12.8, 5.9, 1.5 Hz), 5.77ꢀ3.65 (1H, m), 3.67 (3H, s),
3.17(3H, s), 2.50 (2H, t, J = 7.5 Hz), 1.92ꢀ1.80 (2H, m), [olefin cis:
trans =1:6 δ 1.71 (3H, dd, J = 6.4, 1.7 Hz) or 1.66 (3H, dd, J = 7.0, 1.8 Hz)].
13C NMR (CDCl3, 100 MHz): δ 174.4, 135.3, 131.6, 131.4, 128.8, 127.6
(m), 116.2, 79.3, 73.1 (m), 68.9, 61.2, 32.4 (m), 30.3, 30.1 (m), 27.8, 17.8,
13.5 (m). FTIR (NaCl, thin film): 2963 (s), 2861 (m), 1667 (s), 1417 (m),
1080 (m), 998 (m) cmꢀ1. HRMS (DART, [M þ H]þ): found 228.1605,
calcd for C12H22NO3 228.1600.
(E,Z)-4-(Allyloxy)-1-(pyridin-2-yl)hept-5-en-1-one (27). The
general procedure for addition of 2-bromopyridine to a Weinreb amide
was followed with 2-bromopyridine (96 μL, 1.0 mmol) and n-BuLi
(0.25 mL, 0.60 mmol, 2.3 M in hexanes) in Et2O (2.5 mL) followed by
Weinreb amide 36 (114 mg, 0.50 mmol) in Et2O (10 mL). The reaction
mixture was purified by silica gel chromatography (2 cm ꢁ10 cm, 10% Et2O
in hexanes) to provide pyridyl ketone 27 (65.8 mg, 53% yield) as a clear
colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.68 (1H, ddd, J= 4.8, 1.8, 0.9
Hz), 8.02 (1H, dt, J = 7.9, 1.1 Hz), 7.82 (1H, td, J = 7.7, 1.7 Hz), 4.45 (1H,
ddd, J = 7.5, 4.8, 1.3 Hz), 5.91ꢀ5.80 (1H, m), 5.69ꢀ5.58 (1H, m),
5.39ꢀ5.31 (1H, m), 5.23 (1H, dq, J = 17.2, 1.8 Hz), 5.13ꢀ5.07 (1H, m),
4.04ꢀ3.98 (1H, m), 3.28 (2H, ddd, J = 19.1, 9.6, 8.1 Hz), 2.10ꢀ1.86 (2H,
m), [olefin cis:trans =1:3.8 δ 1.70 (3H, dd, J = 6.4, 1.7 Hz) or 1.65 (3H, dd,
J = 6.8, 1.7 Hz)]. 13C NMR (CDCl3, 100 MHz): δ 201.7, 153.6, 148.9,
136.8, 135.3, 131.7, 129.0, 127.0, 121.8, 116.4, 79.6, 69.0, 33.9, 30.1, 17.8.
FTIR (NaCl, thin film): 3076 (w), 2947 (m), 2860 (m), 1696 (s), 1584
(w), 1438 (w), 1080 (s), 995 (w), 923 (w) cmꢀ1. HRMS (DART, [M þ
H]þ): found 246.1493, calcd for C15H20NO2 246.1494.
1-(Pyridin-2-yl)-4-vinyldec-9-en-1-one (25). To a stirring
solution of t-BuLi (0.90 mL, 1.0 mmol, 1.18 M in pentane) in Et2O
(1.0 mL) at ꢀ78 °C was added iodine 33b (150 mg, 0.50 mmol). After 30
min, a solution of N-methoxy-N-methyl-2-pyridinecarboxamide18 (90 mg,
0.53 mmol) in Et2O (0.5 mL) was added to the reaction mixture by syringe.
The reaction was allowed to stir at ꢀ78 °C for 10 min and then allowed to
warm to room temperature. When the pyridyl ketone had vanished by TLC
(100% Et2O) (∼2 h), the reaction was quenched with NH4Cl (satd)
(3 mL) and extracted with Et2O (3 ꢁ 50 mL) and brine (3 ꢁ 50 mL). The
organic layer was dried over MgSO4 and concentrated. The crude product
was purified by silica gel chromatography (2 cm ꢁ10 cm, hexanes to 10%
Et2O in hexanes) to provide pyridyl ketone 25 (75.9 mg, 55% yield) as a
clear colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.76 (1H, ddd, J = 5.2,
1.8, 0.9 Hz), 8.04 (1H, dt, J= 7.9, 1.1 Hz), 7.82 (1H, td, J= 7.7, 1.6 Hz), 7.45
(1H, ddd, J = 7.5, 4.8, 1.3 Hz), 5.80 (1H, ddt, J = 17.0, 10.3, 6.8 Hz), 5.54
(1H, ddd, J = 16.3, 10.8, 8.8 Hz), 5.02ꢀ4.90 (4H, m), 3.20 (2H, t, J = 7.7
Hz), 2.10ꢀ1.98 (3H, m), 1.89ꢀ1.79 (1H, m), 1.7ꢀ1.58 (1H, m),
1.48ꢀ1.22 (6H, m). 13C NMR (CDCl3, 100 MHz): δ 202.2, 153.6,
149.0, 142.7, 139.1, 136.8, 127.0, 121.8, 115.1, 114.3, 43.9, 35.7, 35.0, 33.9,
29.2, 29.1, 26.8. FTIR (NaCl, thin film): 3073 (m), 2975 (m), 2945 (m),
2859 (m), 1698 (s), 1640 (w), 1585 (w), 995 (m), 913 (m) cmꢀ1. HRMS
(DART, [M þ H]þ): found 258.1848, calcd for C17H24NO 258.1858.
(()-(2aS*,2a1S*,4aS*,8aR*)-2a-(Pyridin-2-yl)decahydro-
1H-azuleno[1,8-bc]furan-1-one (26). The general tandem RCM/
HPK procedure was followed with diene 25 (39.7 mg, 0.150 mmol). The
reaction mixture was purified by silica gel chromatography (1 cm ꢁ
5 cm, 50% Et2O in hexanes with 1% AcOH) to provide lactone 26 (28.1
mg, 71% yield) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ 8.60 (1H,
ddd, J = 4.8, 1.7, 0.9 Hz), 7.66 (1H, td, J = 7.9, 1.8 Hz), 7.44 (1H, d, J =
8.1 Hz), 7.19 (1H, ddd, J = 7.5, 4.9, 1.1 Hz), 2.90ꢀ2.74 (2H, m), 2.41
(1H, dd, J = 13.9, 8.4 Hz), 2.28ꢀ2.16 (2H, m), 2.08ꢀ1.92 (3H, m),
1.92ꢀ1.78 (1H, m), 1.72 (1H, dd, J = 12.1, 8.6 Hz), 1.62ꢀ1.51 (1H, m),
1.36ꢀ1.16 (4H, m). 13C NMR (CDCl3, 100 MHz): δ 179.4, 162.7,
149.6, 136.6, 122.4, 118.8, 95.8, 58.5, 43.6, 42.2, 40.0, 34.6, 34.5, 31.2,
28.1, 26.0. FTIR (NaCl, thin film): 2949 (m), 2897 (m), 2860 (m), 1776
(s), 1588 (w), 1468 (w), 1435 (w), 1315 (w), 1209 (m), 1185 (m), 1152
(m), 1065 (m), 993 (m), 782 (m) cmꢀ1. HRMS (DART, [M þ H]þ):
found 258.1497, calcd for C16H20NO2 258.1494.
(()-(2aR*,4aS*,6bS*)-6a-Pyridin-2-ylhexahydro-1,6-dioxa-
cyclopenta[cd]pentalen-2(2aH)-one (28). The general tandem
RCM/HPK procedure was followed with diene 27 (37.4 mg, 0.150
mmol). The reaction mixture was purified by silica gel chromatography
(1 cm ꢁ5 cm, 75% Et2O in hexanes, 1% AcOH) to provide lactone 28
(E,Z)-4-Hydroxy-N-methoxy-N-methylhept-5-enamide (35).
To a stirring solution of MeNHOMe HCl (137 mg, 1.40 mmol) in
1
(18.0 mg, 51% yield) as a brown oil. H NMR (CDCl3, 400 MHz):
3
CH2Cl2 (2.6 mL) at 0 °C was added AlMe3 (0.70 mL, 1.4 mmol, 2.0 M
in toluene). The reaction mixture was stirred for 15 min, at which time a
solution of lactone 3425 (88.3 mg, 0.7 mmol) in CH2Cl2 (2.6 mL) was
added in one portion. The reaction was allowed to warm to room
temperature over ∼12 h. The reaction was quenched with 2 M HCl
(10 mL) and extracted with CH2Cl2 (3 ꢁ 50 mL) and brine (3 ꢁ 50 mL).
The organic layer was dried over MgSO4 and concentrated. The product
was purified by silica gel chromatography (1 cm ꢁ 5 cm, 100% Et2O) to
provide 35 (74.6 mg, 57% yield) as a clear yellow oil. 1H NMR(CDCl3, 400
δ 8.57 (1H, ddd, J = 4.9, 1.8, 1.1 Hz), 7.70 (1H, td, J = 9.5, 1.8 Hz), 7.53
(1H, dt, J = 7.9, 0.9 Hz), 7.22 (1H, ddd, J = 7.5, 4.8, 1.1 Hz), 4.73 (1H,
ddd, J = 7.0, 5.1, 2.6 Hz), 4.46 (1H, d, J = 9.1 Hz), 3.93 (1H, dd, J = 9.2,
6.4 Hz), 3.72 (1H, dd, J = 9.2, 6.6 Hz), 3.25 (1H, ddd, J = 9.3, 6.4, 1.1
Hz), 2.48ꢀ2.40 (2H, m) 2.34ꢀ2.12 (2H, m). 13C NMR (CDCl3, 100
MHz): δ 178.5, 162.0, 149.5, 136.9, 122.7, 118.9, 95.4, 87.7, 73.7, 56.7,
47.6, 40.5, 31.5. FTIR (NaCl, thin film): 2968 (s), 2874 (s), 1775 (s),
1589 (w), 1589 (w), 1470 (w), 1435 (w), 1060 (s) cmꢀ1. HRMS
(DART, [M þ H]þ): found 232.0972, calcd for C13H14NO3 232.0972.
3651
dx.doi.org/10.1021/jo200359c |J. Org. Chem. 2011, 76, 3644–3653

The Journal of Organic Chemistry
FEATURED ARTICLE
Ethyl 3-(Allyloxymethyl)pent-4-enoate (38). A mixture of
alcohol 3727 (1.38 g, 10.7 mmol), triethyl orthoacetate (13.0 mL, 75.0
mmol), and propionic acid (112 μL, 1.50 mmol) was warmed in a 130 °C
oil bath for 24 h. The reaction was quenched with HCl (aq) (2 N, 15 mL)
and extracted with Et2O (3 ꢁ 50 mL) and saturated NaHCO3 (aq) (3 ꢁ
50 mL). The organic layer was dried over MgSO4 and concentrated. The
ester 38 (1.60 g, 75% yield) was used without further purification. For
purposes of characterization, the crude product was purified by silica gel
chromatography (10% Et2O in hexanes). 1H NMR (CDCl3, 400 MHz):
δ 5.88 (1H, qt, J = 10.4, 5.5 Hz), 5.75 (1H, ddd, J = 18.1, 10.4, 7.9 Hz), 5.26
(1H, dq, J = 17.2, 1.7 Hz), 5.19ꢀ5.06 (3H, m), 4.12 (2H, q, J = 7.1 Hz),
3.99ꢀ3.95 (2H, m), 3.40 (1H, dd, J = 9.3, 5.7 Hz), 3.35 (1H, dd, J = 9.3,
7.1 Hz), 2.91ꢀ2.82 (1H, m), 2.55 (1H, dd, J = 15.1, 6.1 Hz), 2.34 (1H, dd,
J = 15.4, 8.2 Hz), 1.24 (3H, t, J = 7.4 Hz). 13C NMR (CDCl3, 100 MHz): δ
172.4, 138.1, 134.8, 116.8, 116.2, 72.8, 72.0, 60.4, 40.5, 36.7, 14.4. FTIR
(NaCl, thin film): 3079 (w), 2981 (m), 2863 (m), 1738 (s), 1644 (w),
quenched with NH4Cl (satd) (5 mL) and extracted with Et2O (3 ꢁ
25 mL) and brine (3 ꢁ 25 mL). The organic layer was dried over MgSO4
and concentrated. The crude product was purified by silica gel chroma-
tography (2 cmꢁ10 cm, 33% Et2O inhexanes to 50% Et2O in hexanes) to
provide pyridyl ketone 29(103.9mg, 38% yield) as a clear colorlessoil. 1H
NMR (CDCl3, 400 MHz): δ 8.68 (1H, ddd, J = 4.8, 1.8, 0.9 Hz), 8.02
(1H, dt, J = 7.9, 0.9 Hz), 7.82 (1H, td, J = 7.5, 1.7 Hz), 7.45 (1H, ddd, J =
7.5, 4.8, 1.3 Hz), 5.90 (1H, ddt, J = 17.2, 10.4, 5.5 Hz), 5.69 (1H, ddd, J =
17.2, 10.3, 8.4 Hz), 5.26 (1H, dq, J= 17.4, 1.8 Hz), 5.18ꢀ5.06 (3H, m), 3.98
(2H, dt, J = 5.5, 1.5 Hz), 3.42 (2H, d, J = 6.4 Hz), 3.25 (2H, t, J = 7.5 Hz),
2.48ꢀ2.40 (1H, m), 2.03ꢀ1.93 (1H, m), 1.77ꢀ1.66 (1H, m). 13C NMR
(CDCl3, 100 MHz): δ 201.9, 153.6, 149.0, 139.6, 136.9, 135.1, 127.0, 121.8,
116.8, 116.5, 73.9, 72.1, 44.0, 35.5, 25.6. FTIR (NaCl, thin film): 3075 (w),
2978 (w), 2952 (w), 2865 (m), 1697 (s), 1584 (w), 1365 (w), 1103 (m),
995 (m), 919 (m), 776 (w) cmꢀ1. HRMS (DART, [M þ H]þ): found
246.1505, calcd for C15H20NO2 246.1494.
(()-(4aR*,7aS*,7bS*)-2a-Pyridin-2-yloctahydro-1H-2,6-di-
oxacyclopenta[cd]inden-1-one (30). The general tandem RCM/
HPK procedure was followed with diene 29 (37.1 mg, 0.150 mmol). The
reaction mixture was purified by silica gel chromatography (1 cm ꢁ
5 cm, 40% Et2O in hexanes with 1% AcOH) to provide lactone 30 (28.1
mg, 44% yield) as a gray solid. 1H NMR (CDCl3, 400 MHz): δ 8.59 (1H,
ddd, J = 4.8, 1.6, 0.9 Hz), 7.71 (1H, td, J = 7.9, 1.8 Hz), 7.55 (1H, dt, J =
7.9, 1.1 Hz), 7.23 (1H, ddd, J = 7.5, 4.8, 1.3 Hz), 4.43 (1H, d, J = 2.1 Hz),
3.96 (1H, d, J = 2.1 Hz), 3.64 (1H, dd, J = 12.0, 3.9 Hz), 3.52 (1H, dd, J =
11.9, 4.2 Hz), 3.41 (1H, t, J = 10.1 Hz), 2.58 (1H, dd, J = 10.3, 4.0 Hz),
2.39ꢀ2.21 (3H, m), 2.08ꢀ1.95 (1H, m), 1.95ꢀ1.85 (1H, m). 13C NMR
(CDCl3, 100 MHz): δ 177.5, 160.4, 149.5, 136.9, 122.9, 119.8, 96.3,
68.4, 65.6, 43.3, 39.9, 37.7, 37.0, 28.7. FTIR (NaCl, thin film): 3053 (w),
2957 (w), 2858 (w), 1768 (s), 1589 (w), 1468 (w), 1181 (w), 1150 (w),
1119 (w), 1063 (w), 998 (w), 752 (w) cmꢀ1. HRMS (DART, [M þ
H]þ): found 246.1135, calcd for C14H16NO3 246.1130. Mp: 88ꢀ90 °C.
1420 (m), 1371 (m), 1252 (m), 1179 (m), 1102 (m), 921 (m) cmꢀ1
.
HRMS (DART, [M þ H]þ): found 199.1336, calcd for C11H19O3
199.1334.
3-(Allyloxymethyl)pent-4-en-1-ol (38a). To a stirring solution
of ester 38 (993 mg, 5.0 mmol) in Et2O (13 mL) at ꢀ78 °C was added
LAH (381 mg, 10.0 mmol). The reaction was allowed to warm to room
temperature over ∼12 h and was quenched according to the procedure
of Micovic by sequential addition of 0.4 mL of H2O, 0.4 mL of 15%
NaOH, and 1.2 mL of H2O.33 The white solid was filtered and
concentrated under vacuum to provide ester 38a (408.9 mg, 52% yield)
as a clear colorless oil. The material was used without further purifica-
tion. To provide analytically pure material the crude material was
purified by silica gel chromatography (25% Et2O in hexanes). 1H
NMR (CDCl3, 400 MHz): δ 5.90 (1H, ddt, J = 17.2, 10.4, 5.7 Hz),
5.72 (1H, ddd, J = 17.4, 10.4, 8.4 Hz), 5.27 (1H, dq, J = 17.2, 1.7 Hz),
5.18 (1H, J = 10.4, 1.3 Hz), 5.13 (1H, dd, J = 1.8, 0.9 Hz), 5.07 (1H, ddd,
J = 10.4, 1.6, 0.9 Hz), 3.99 (2H, m), 3.75 ꢀ 3.60 (2H, m), 3.44 (1H, dd,
J = 9.2, 5.5 Hz), 3.37 (1H, dd, J = 9.3, 7.3 Hz), 2.55ꢀ2.45 (1H, m), 2.06
(1H, t, J = 5.9 Hz), 1.76 (1H, ddt, J = 11.7, 7.5, 5.9 Hz), 1.65 (1H, ddt, J =
13.9, 7.7, 6.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 139.6, 134.6, 117.3,
115.9, 74.0, 72.2, 61.2, 41.7, 35.3. FTIR (NaCl, thin film): 3418 (br),
3356 (b), 3076 (w), 2952 (m), 2872 (s), 1643 (m), 1421 (m), 1349 (m),
1057 (s), 998 (s), 919 (s) cmꢀ1. HRMS (DART, [M þ H]þ): found
157.1231, calcd for C9H17O2 157.1229.
’ ASSOCIATED CONTENT
S
Supporting Information. X-ray crystallographic data and
b
1H NMR and 13C NMR spectra are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
3-(Allyloxymethyl)-5-iodopent-1-ene (39). The general iodi-
nation procedure was followed with alcohol 38a (300 mg, 1.90 mmol),
iodine (733 mg, 2.90 mmol), triphenylphosphine (905 mg, 3.50 mmol),
imidazole (273 mg, 4.00 mmol), acetonitrile (2.4 mL), and Et2O
(4.0 mL). The reaction mixture was purified by silica gel chromatogra-
phy (2 cm ꢁ10 cm, 50% Et2O in hexanes) to provide iodide 39 (254.4
mg, 50% yield) as a clear colorless oil. 1H NMR (CDCl3, 400 MHz): δ
5.90 (1H, ddt, J = 17.2, 10.6, 5.7 Hz), 5.60 (1H, ddd, J = 17.2, 10.3, 8.6
Hz), 5.26 (1H, dq, J = 17.2, 1.7 Hz), 5.20ꢀ5.10 (3H, m), 3.96 (2H, dq,
J = 5.5, 1.3 Hz), 3.38 (2H, qd, J = 9.3, 5.9 Hz), 3.27 (1H, ddd, J = 9.5, 7.9,
5.1 Hz), 3.10 (1H, dt, J = 9.5, 8.1 Hz), 2.46 (1H, m), 2.09 (1H, dtd, J =
14.1, 8.1, 4.4 Hz), 1.80 (1H, dddd, J = 14.5, 9.3, 7.7, 5.1 Hz). 13C NMR
(CDCl3, 100 MHz): δ 138.1, 134.8, 117.2, 117.0, 73.2, 72.2, 45.1, 35.3,
4.8. FTIR (NaCl, thin film): 3076 (w), 3025 (w), 2960 (m), 2862 (s),
1728 (w), 1643 (w), 1421 (w), 1099 (s), 920 (s) cmꢀ1. HRMS (DART,
[M þ H]þ): found 267.0253, calcd for C9H16IO 267.0246.
Corresponding Author
*E-mail: marc.snapper@BC.edu.
’ ACKNOWLEDGMENT
We thank the National Science Foundation (CHE-0911212)
for financial support. We also acknowledge Schering-Plough for
X-ray facility support, Dr. Bo Li and Stephanie Ng for crystal-
lographic studies, and Materia for the gift of metathesis catalyst.
’ REFERENCES
(1) (a) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.—Eur. J. 2009,
15, 12168–12179. (b) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev.
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2004, 76, 1967–1983. (d) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan,
G. C. Chem. Rev. 2005, 105, 1001–1020. (e) Ajamian, A.; Gleason, J. G.
Angew. Chem., Int. Ed. 2004, 43, 3754–3760. (f) Dragutan, V.; Dragutan, I.
J. Organomet. Chem. 2006, 691, 5129–5147. (g) Shindoh, N.; Takemoto, Y.;
Takasu, K. Chem.—Eur. J. 2009, 15, 12168–12179.
(2) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1995, 34, 2039–2041. (b) Furstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012–3043. (c) Grubbs, R. H.; Trnka, T. M. Acc. Chem.
Res. 2001, 34, 18–29.
4-(Allyloxymethyl)-1-(pyridin-2-yl)hex-5-en-1-one (29). To
a solution of the iodine 39 (247.0 mg, 0.930 mmol) stirring in Et2O
(3.3 mL) at ꢀ78 °C was added t-BuLi (2.20 mL, 1.90 mmol, 0.86 M in
pentane). After 1 h, a solution of N-methoxy-N-methyl-2-pyridinecar-
boxamide18 (140 mg, 0.840 mmol) in Et2O (1.5 mL) was added to the
reactionmixture by syringe. The reactionwas allowedtostir atꢀ78 °C for
10 min and then allowed to warm to room temperature. When the pyridyl
ketone had vanished by TLC (100% Et2O) (∼2 h), the reaction was
3652
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The Journal of Organic Chemistry
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