Facile access to cyclooctanoid ring systems via microwave-assisted tandem 6-exo dig cyclization-rearrangement sequence

Article abstract of DOI:10.1016/j.tet.2014.02.089

Appropriately substituted 5-alkyn-1-ol systems bearing a nitrile moiety at the triple bond serve as versatile precursors to a variety of cyclooctenone derivatives via a 'one-pot' base-catalyzed oxyanionic 6-exo dig cyclization/Claisen rearrangement sequence under microwave irradiation. It was found that the initially formed cyclic intermediate consists of a mixture of endo and exocyclic isomers, which appear to be in equilibrium under the reaction conditions. However, the only observed products from these reactions are α-cyano-substituted cyclooctenones, derived from the exocyclic dihydrofuran intermediates.

Full text of DOI:10.1016/j.tet.2014.02.089

Tetrahedron 70 (2014) 4147e4155
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile access to cyclooctanoid ring systems via microwave-assisted
tandem 6-exo dig cyclizationerearrangement sequence
*
Aaron W. Feldman, Sami I. Ovaska, Timo V. Ovaska
Department of Chemistry, Connecticut College, 270 Mohegan Avenue, New London, CT 06320, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Appropriately substituted 5-alkyn-1-ol systems bearing a nitrile moiety at the triple bond serve as
versatile precursors to a variety of cyclooctenone derivatives via a ‘one-pot’ base-catalyzed oxyanionic 6-
exo dig cyclization/Claisen rearrangement sequence under microwave irradiation. It was found that the
initially formed cyclic intermediate consists of a mixture of endo and exocyclic isomers, which appear to
be in equilibrium under the reaction conditions. However, the only observed products from these re-
Received 20 January 2014
Received in revised form 26 February 2014
Accepted 28 February 2014
Available online 6 March 2014
actions are
a-cyano-substituted cyclooctenones, derived from the exocyclic dihydrofuran intermediates.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Despite their obvious medicinal relevance, efforts to access
cyclooctanoid natural products by synthetic means have been slow
Cyclooctanoid carbocyclic compounds are widespread in nature
and many of them exhibit significant biological activity.1 They have
been isolated from various sources, including marine organisms,
pathogenic fungi, terrestrial plants, and insects. To date, well over
100 structurally diverse cyclooctanoid natural products with
varying degrees of complexity have been identified and charac-
terized.1 Several representative examples of these are shown in
Fig. 1.
to emerge primarily because of difficulties associated with the
construction of cyclooctane ring systems. As conventional annula-
tion strategies are largely ineffective in this context, most of the
methods currently available for the synthesis of eight-membered
rings involve various fragmentation reactions of existing polycyclic
structures2,3 and several cycloaddition strategies.4
We have recently demonstrated that a variety of cycloheptanoid
fused ring systems may be prepared through a known5 but largely
Fig. 1. Representative examples of biologically active cyclooctanoid natural products.
ignored tandem reaction sequence that involves a base-catalyzed
intramolecular cyclization of appropriately substituted 4-pentyn-
1-ols, followed by in situ Claisen rearrangement of the intermediate
* Corresponding author. Tel.: þ1 860 439 2488; fax: þ1 860 439 2477; e-mail
addresses: tvova@conncoll.edu, timo.ovaska@conncoll.edu (T.V. Ovaska).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.089

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A.W. Feldman et al. / Tetrahedron 70 (2014) 4147e4155
2-alkylidenetetrahydrofurans (Scheme 1).6 The reaction was found
to be quite general, allowing the rapid construction of mono-, di-,
tri-, and tetracyclic carbocyclic structures. Although anionic 5-exo
dig cyclizations involving oxygen nucleophiles have been known
since the early 1950s,7 these transformations are generally difficult
to achieve due to the reversibility and unfavorable equilibria as-
sociated with such isomerizations, particularly with unactivated
alkynes. In addition, the initially formed exocyclic vinyl ethers are
often unstable8 and isomerize easily to form the corresponding
endocyclic derivatives.9
failed completely. For example, treatment of alkynol 1 with a base
under microwave irradiation produced no detectable amounts of 2
even after prolonged heating (Scheme 2) and the starting material
was recovered quantitatively. The reason for the reaction to fail is
almost certainly due to the inability of the 5-alkyn-1-ol 1 to un-
dergo the initial 6-exo cyclization. In fact, Paquette et al.13 and
Petasis14 have previously demonstrated that preformed allyl vinyl
ether precursors with terminal exocyclic double bonds, prepared
from d
-valerolactone derivatives via the Tebbe15 or Petasis14 re-
actions, are indeed capable of undergoing [3,3]-sigmatropic rear-
rangements. The failure of the examined 5-alkyn-1-ol system 1 to
cyclize is consistent with the observed trend that 6-exo isomeri-
zations are generally more sluggish than the corresponding 5-exo
processes.16 It was therefore obvious that some degree of initial
activation of the triple bond was required in order for the 6-exo
oxyanionic cyclization to proceed and form the requisite 2-
alkylidenetetrahydropyranyl intermediate. Thus, various 5-alkyn-
1-ols bearing electron withdrawing ester or nitrile substituents at
the triple bond terminus were investigated.
Scheme 1. General strategy to cycloheptane-containing polycycles via sequential cy-
clization/Claisen rearrangement reaction.
These problems may be largely avoided by taking advantage of
an appropriately substituted 4-alkyn-1-ol substrate that undergoes
cycloisomerization under basic conditions, forming a transient 2-
alkylidenetetrahydrofuran species, which rearranges spontane-
ously via a thermally promoted 3,3-sigmatropic process.5 It is
noteworthy that the initial intramolecular cyclization requires the
use of a catalytic base that allows for rapid protonation of the in-
termediate vinyl anion species, and renders the cycloisomerization
process irreversible (Scheme 1). Using this strategy as the key ring
forming step, the total syntheses of (ꢀ)-frondosin C,10 (ꢁ)-frondo-
sin B11 and the formal synthesis of (ꢀ)-frondosin A12 were recently
achieved in our laboratory.
At the outset of the current study, it was envisioned that the
methodology successfully developed for the generation of cyclo-
heptanoid structures could also be used for the construction of
cyclooctanoid ring systems, by simply employing appropriately
substituted 5-hexyn-1-ols (instead of 4-pentyl-1-ols) as starting
materials.
Scheme 2. Failed 6-exo dig cyclization/Claisen rearrangement reaction.
It should be noted that, although a few strictly oxyanionic 5-exo
dig cyclizations of this type (oxa-Michael reaction) have been re-
ported in the literature17 (including by us18) the corresponding 6-
exo cyclizations are almost non-existent.19 However, activation of
triple bonds by transition metal catalysts is more common and
various gold catalysts, in particular, have been utilized extensively
for intramolecular hydroalkoxylations to generate a THF and THP
derivatives via both 5-exo and 6-exo dig modes of cyclization.20
2.1. Ester activation
2. Results and discussion
To test the potential of the 6-exo dig cyclization/Claisen rear-
rangement sequence as a route to cyclooctane ring systems, we
initially investigated the cyclization of allyl alcohols onto alky-
Our initial attempts to employ several homologous 5-hexyn-1-
ols as precursors to eight-membered ring containing systems via
a base-catalyzed 6-exo cyclization/Claisen rearrangement sequence
noates. Thus, the carbethoxy derivative
6 was prepared in
a straightforward fashion as shown in Scheme 3.
Scheme 3. 6-exo cyclization/Claisen rearrangement of acetylenic ester 6.

A.W. Feldman et al. / Tetrahedron 70 (2014) 4147e4155
4149
Upon treatment with catalytic LHDMS (10 mol %) in DME and
exposure to microwave irradiation for 1 h, it was found that the
desired cyclooctenone 821 was formed in a modest 44% isolated
yield along with ca. 15% of an unexpected cyclohexene derivative
9.22 This byproduct was presumably formed as a result of an exo/
endo double bond isomerization followed by subsequent 3,3-
sigmatropic rearrangement of the resulting allyl vinyl ether 7b.
This isomerization is most likely base-catalyzed, producing a fully
conjugated enolate anion intermediate via
g-deprotonation
(Scheme 4). In fact, we have observed the formation of both 7a and
7b with the endocyclic derivative predominating when 6 was
stirred in the presence of catalytic LHDMS even at room tempera-
ture. Interestingly, the TBS-protected alcohol 5 was also converted
to 7b upon stirring in the presence of TBAF at room temperature
overnight.
Scheme 5. 6-exo Cyclization/Claisen rearrangement of a cyano derivative.
Scheme 4. Possible mechanism for the base-catalyzed exo/endo isomerization.
Although similar exo/endo isomerization reactions involving 2-
methylidene tetrahydrofuran derivatives (formed via 5-exo dig
cyclization) are known to occur under high temperature condi-
tions,9 we have previously not observed [3,3]-rearrangement re-
actions involving endocyclic tetrahydrofuran intermediates in any
of the systems examined. It is reasonable to assume that, in the case
of 7b, the increased flexibility of a six-membered dihydropyran
system compared to an analogous five-membered tetrahydrofuran
LHMDS) in 80% isolated yield. Significantly, no products analogous to
9 were detected in the reaction mixture.
It is noteworthy that the four-step sequence from alcohol 423 to
the corresponding cyano derivative 10 may be performed as a ‘one-
pot’ reaction without the need for isolation of the intermediate
products. This process involves transient protection of 4 as a TMS
ether with TMSCN under neutral conditions, which enables the
selective deprotonation of the terminal acetylene with n-BuLi and
subsequent cyanylation with PhOCN. Workup with 10% aq HF (or
Amberlyst-15) removes the TMS protecting group, affording 10.
Other analogues of 10 were prepared by coupling various vinyl-
lithum reagents, derived from the corresponding vinyl iodides or
bromides by low-temperature lithiumehalogen exchange, with
appropriate acetylenic aldehydes. Systems bearing a cyclic acetal
moiety as part of the 5-alkyn-1-ol system were prepared as shown
in Scheme 6 starting with the known acetal 12.24
system allows the p-bonds of the allyl vinyl ether system to become
proximal enough for this alternative mode of rearrangement to
occur. Consistent with our observations, rearrangement of the
exocyclic intermediate should be faster because it can proceed
through a chair-like transition state while the endocyclic in-
termediate would need to adopt a boat-like transition state.
It should be noted that 6 also cyclized readily when exposed to
catalytic AuCl3 at room temperature,20b producing a 1.6 to 1 ratio of
Scheme 6. Preparation of acetal-containing 5-alkyn-1-ol systems.
endo and exo isomers, respectively; however, when the reaction
mixture was subsequently heated in the microwave oven (in the
presence of the Au catalyst), extensive decompositionwas observed.
All of the cyano-substituted 5-hexyn-1-ol systems studied so far
were found to undergo clean conversion to the desired cyclo-
octanone derivatives via the 6-exo cyclization/Claisen rearrange-
ment process. These experiments demonstrated that fused 5e8
ring systems (Table 1, entries 3 and 6) may also be accessed through
this methodology in a straightforward fashion.
2.2. Nitrile activation
It should be emphasized that this chemistry is unique in that it
allows the direct formation of cyclooctenone derivatives bearing
the versatile a-cyano ketone functionality, which offers ample op-
portunities for further functionalization and structural di-
versification. Aside from the many separate functional group
In addition to the to ester derivative 6, analogous cyano-
substituted acetylenes were also investigated. Thus, compound 10,
readily prepared from allylic alcohol 4 (Scheme 5), was smoothly
converted to the desired cyclooctanone derivative 11 under mi-
crowave irradiation in the presence of catalytic base (10 mol %

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A.W. Feldman et al. / Tetrahedron 70 (2014) 4147e4155
Table 1
the reactions at different temperatures followed by careful analysis
of the resulting product mixtures. The formation of all four prod-
ucts (12a, 12b, 12c, 11) monitored by TLC and the relative abun-
dance of each isomer was determined by NMR analysis (see
Experimental section). The 1H chemical shift assignments for the
E and Z exocyclic intermediates (12a and 12c) are based on those
previously reported for similar systems.26
Preparation of cyclooctanoid ring systems via sequential 6-exo dig cyclization/
Claisen rearrangement process
It was also found that compound 10 cyclizes readily even at
room temperature when exposed to 10 mol % LHDMS in DME.
Under these conditions, 10 underwent a clean cycloisomerization
reaction in 4 h to produce a mixture of 12a and 12b with only trace
amounts of the Z-exocyclic isomer 12c present (Scheme 7). It
should be noted that there is no reaction without added base and 10
is stable for extended periods of time when stored at room
temperature.
Entry
1
Allyl alcohol
Product
Yield (%)
80
2
3
75
As expected, the formation of the cyclooctenone product 11 is
highly temperature dependent as evidenced by a series of experi-
ments conducted in the microwave oven at temperatures ranging
from 150 ꢂC to 200 ꢂC. All experiments were conducted in anhy-
drous DME over a period of 1 h in the presence of 10 mol % LHMDS
(1.0 M solution in THF). Thus, at 150 ꢂC, approximately 13% of the
product mixture consisted of the cyclooctenone 10, the balance of
the reaction consisting of nearly equal amounts of the endo and exo-
cyclic intermediates 12a and 12b. Some isomerization of the E and Z
isomers 12a/c was also observed under these conditions. As tem-
perature was raised, the amount of 11 also increased steadily while
concentrations of the cyclized intermediates decreased accordingly.
At 190 ꢂC, cyclooctenone 11 and the endocyclic intermediate 12b
made up 72% and 25% of the product mixture, respectively, while
only approximately 3% of the (E)-exocyclic intermediate 12a was
found to be present. At 200 ꢂC, nearly 86% of 10 had been converted
to the desired cyclooctenone 11, the balance of the reaction con-
sisting of just the endocyclic intermediate 12b. The ideal temper-
ature for this reaction appears to be 210 ꢂC under which conditions
full conversion of 10 to 11 was observed. Since 11 is derived from
the exocyclic dihydropyran species 12a (or 12c) none of which was
present at temperatures at or above 200 ꢂC, it is clear that under
these high temperature conditions endo/exo isomerization in-
volving 12b serves as a source for the requisite exocyclic species,
which then cyclizes rapidly to produce 11. The results from these
experiments are shown graphically in Fig. 2.
64a
4
5
79
84
6
78b
a
Isolated as a 2.7:1 mixture of diastereomers.
Isolated as a 1:1 mixture of diastereomers.
We also analyzed reactions that were conducted at 210 ꢂC,
monitoring the product composition versus time. It was found that
b
Scheme 7. 6-exo dig Cyclization of 10 at room temperature.
manipulations of the ketone carbonyl and cyano groups, there are
a number of other possible transformations unique to the -cyano
a
ketone system that provide access to a variety of functionalized
derivatives, including heterocyclic structures.25
2.3. Rate studies
Although the cyano derivatives investigated thus far appear to
undergo clean tandem 6-exo cyclization/Claisen rearrangement
reactions to afford the expected cyclooctanoid derivatives, closer
examination of these processes revealed that both endocyclic
dihydropyranyl and tetrahydropyranyl exocyclic species analogous
to 7a and 7b were intermediates in the reaction. This was con-
firmed by using compound 10 as a model system and conducting
Fig. 2. Temperature dependent formation of reaction products upon heating 10 in the
presence of catalytic base (LHDMS).

A.W. Feldman et al. / Tetrahedron 70 (2014) 4147e4155
4151
only after 15 min under these conditions, the product mixture
consisted of approximately 75% of 11 and 25% 12b; no exocyclic
intermediates (12a, 12c) were observed. After 30 min at 210 ꢂC,
more than 90% of the product mixture consisted of 11; however, full
conversion requires 60 min. These results are shown graphically in
Fig. 3.
All microwave experiments were conducted in Biotage Initiator
Microwave Synthesizer, equipped with an infrared temperature
control system. All microwave reactions were performed in sealed
10 mL or 5 mL microwave vials.
Tetrahydrofuran (THF) and diethyl ether were freshly distilled
under N2 from dark blue solutions of sodium benzophenone ketyl.
Dimethoxyethane (DME), dichloromethane (DCM), TMSCl, and
Et3N were freshly distilled under N2 from calcium hydride. Bulk
solvents were purchased from Fisher or VWR.
All starting reagents were purchased from SigmaeAldrich, Acros
or Strem. The concentrations of solutions of n-BuLi, and t-BuLi were
determined by titrations with sec-butyl alcohol using 1,10-
phenanthroline as the indicator following the method of Watson
and Eastham.27 All glassware were flame-dried under an inert at-
mosphere and all reactions were performed under an atmosphere
of dry nitrogen.
4.2. tert-Butyldimethyl(oct-1-en-7-yn-3-yloxy)silane28
Alkyne 423 (2.88 g, 23.2 mmol) was dried over molecular
sieves in DCM and transferred to a round bottom flask contain-
ing DCM (100 mL) at
Fig. 3. Time dependence of product formation on heating 10 at 210 ꢂC in the presence
of catalytic base (LHDMS).
0
ꢂC. Dry triethylamine (3.92 mL,
28.1 mmol) and a catalytic quantity of DMAP were then added
followed by TBSCl (3.89 g, 25.8 mmol). The reaction mixture was
allowed to stir overnight while warming to room temperature.
The reaction was quenched with H2O (20 mL) and the layers
were separated. The aqueous layer was extracted with DCM
(3ꢃ30 mL), the combined organic layers were washed with brine
and dried over MgSO4. The solution was filtered and solvent was
removed under reduced pressure. The resulting residue was
purified by column chromatography (pure hexanes) to give
4.10 g of TBS-protected alcohol (74% yield) as a colorless oil. 1H
3. Conclusion
We have demonstrated that cyano-substituted 5-alkyn-1-ol
systems serve as versatile precursors to a variety of cyclooctenone
derivatives via a microwave-assisted sequential oxyanionic 6-exo
dig cyclization/Claisen rearrangement reaction in the presence of
catalytic base. It was found that the initially formed cyclic in-
termediate consists of a mixture of endo and exocyclic isomers,
which appear to be in equilibrium under the reaction conditions.
Although both the endo and exocyclic intermediates are potentially
capable of undergoing 3,3-sigmatropic rearrangements, the only
NMR (500 MHz, CDCl3)
d
5.80 (ddd, J¼17.2, 10.4, 1.2 Hz, 1H), 5.15
(dt, J¼17.1, 1.2 Hz, 1H), 5.04 (dt, J¼10.2, 1.3 Hz, 1H), 4.16e4.09 (m,
1H), 2.23e2.15 (m, 2H), 1.94 (t, J¼2.6 Hz, 1H), 1.64e1.50 (m, 4H),
0.90 (s, 9H), 0.04 (s, 6H), 0.02 (s, 3H). 13C NMR (125.6 MHz,
observed products from the reactions investigated so far are a-cy-
ano-substituted cyclooctenones, derived from the exocyclic species.
These results demonstrate that isomerization of the endocyclic in-
termediate to the corresponding exocyclic species is faster than
a direct sigmatropic rearrangement, and that the exocyclic in-
termediate, once formed, rearranges more rapidly provided that
enough thermal energy is present.
CDCl3)
d 141.5, 113.8, 84.5, 73.3, 68.3, 37.0, 25.9, 24.1, 18.4, 18.2,
-4.4, -4.9.
4.3. Ethyl 7-(tert-butyldimethylsilyloxy)-8-nonen-2-ynoate (5)
A solution of tert-butyldimethyl(1-octen-7-yn-3-yloxy)silane
(4.68 g, 19.6 mmol) in THF (80 mL) was cooled to ꢁ78 ꢂC, and n-
BuLi (1.6 M, 14.7 mL, 23.6 mmol) was added dropwise via syringe.
The resulting mixture was allowed to stir at this temperature for
30 min. A solution of ethyl chloroformate (8.52 g, 7.47 mL,
78.5 mmol) in 15 mL of THF was then added to the reaction
mixture dropwise via cannula. After 1 h, the reaction quenched
with 10% HCl (5 mL). The solvent was removed under reduced
pressure and the resulting residue was taken up in diethyl ether
(25 mL) and H2O (20 mL), and the layers were separated. The
aqueous layer was then extracted with diethyl ether (3ꢃ25 mL).
The combined ethereal layers were then washed with satd
NaHCO3 (25 mL) and dried over anhydrous MgSO4. The solution
was filtered and solvent was removed under reduced pressure.
The resulting crude oil was purified by column chromatography
(3% ethyl acetate in hexanes) to give 3.85 g of the desired ester 13
Slightly different results were obtained when the analogous
alkynoate 6 was used as the starting material. In this case, the
tandem 6-exo dig cyclization/Claisen rearrangement reaction
afforded a modest yield of the desired cyclooctenone derivative 8.
In addition, the formation of cyclohexenyl ketoester 9, derived via
competing rearrangement of the endocyclic species 7b, was also
observed under these conditions. The difference in the chemical
behavior between the corresponding ester and cyano analogues is
not fully understood at this time.
Our future studies will focus on further probing the synthetic
utility of the oxyanionic 6-exo dig cyclization/Claisen rearrange-
ment sequence as a route to wide variety of cyclooctanoid systems,
including natural products. The results from these studies will be
reported in due course.
4. Experimental
4.1. General
(63%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3)
d 5.77 (ddd,
J¼16.1, 10.3, 5.9 Hz, 1H), 5.14 (dt, J¼17.1, 1.5 Hz, 1H), 5.04 (dt,
J¼10.3, 1.5 Hz, 1H), 4.21 (q, J¼7.07 Hz, 2H), 4.16e4.10 (m, 1H),
2.37e2.31 (m, 2H), 1.68e1.54 (m, 4H), 1.30 (t, J¼7.1 Hz, 3H), 0.89 (s,
1H and 13C NMR spectra were obtained using an Agilent DD2-
500 NMR (500 MHz) spectrometer. Chemical shifts are reported
in units of parts per million (ppm), relative to tetramethylsilane at
9H), 0.04 (s, 3H), 0.02 (s, 3H). 13C NMR (125.6 MHz, CDCl3)
d 153.9,
141.2, 114.1, 89.2, 73.3, 73.1, 61.8, 36.9, 25.9, 23.1, 18.7, 18.2, 14.1,
ꢁ4.4, ꢁ4.9. HRMS (ESI-TOF) m/z [MþNa]þ calcd for C17H30O3SiNa
333.1862; found 333.1857.
d¼0.00 ppm. Coupling constants J are reported in hertz (Hz).

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A.W. Feldman et al. / Tetrahedron 70 (2014) 4147e4155
4.4. Ethyl 7-hydroxynon-8-en-2-ynoate (6)
4.7. 7-Hydroxy-8-nonen-2-ynenitrile (10)
Ester 5 (1.20 g, 3.87 mmol) was dissolved in 14 mL of acetone/
H2O (6:1 ratio), a catalytic amount of pyridinium p-toluenesulfo-
nate (PPTS) was added to the solution, and the reaction mixture
was allowed to stir overnight at 50 ꢂC. Solvent was then removed
under reduced pressure and the resulting residue was taken up in
diethyl ether (15 mL) and H2O (10 mL). Upon separating layers, the
aqueous layer was extracted with diethyl ether (3ꢃ10 mL). The
combined organic layers were washed with brine, dried over an-
hydrous MgSO4, filtered, and the solvent was removed under re-
duced pressure. The remaining crude oil was purified by column
chromatography on silica gel (15% EtOAc/hexanes) to give 0.663 g of
alcohol 14 (88%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3)
Alcohol 4 (0.507 g, 4.08 mmol), dissolved in 2 mL of DCM was
dried over activated molecular sieves and then transferred to
a 20 mL reaction vial via Teflon cannula. The DCM solvent was then
evaporated with the aid of a stream of nitrogen gas, and neat
TMSCN (0.486 g, 4.90 mmol) was added via syringe. After 2 h of
stirring the reaction was judged to be complete by TLC. The neat
solution was then diluted with 6 mL of diethyl ether and nitrogen
gas was bubbled through the solution for 15 min to drive off any
remaining HCN. The mixture was then cooled to ꢁ78 ꢂC and n-BuLi
was added dropwise (1.6 M, 3.10 mL, 4.90 mmol). After 30 min at
this temperature, PhOCN30 (0.633 g, 5.31 mmol) in 4.0 mL diethyl
ether was added dropwise via a syringe. After 30 min of stirring at
this temperature the cooling bath was removed and the mixture
was allowed to warm to room temperature. The reaction mixture
was then diluted with 20 mL of diethyl ether. A solution of 10%
NaOH (10 mL) was then added and the biphasic mixture was stirred
vigorously for 5 min to remove the phenol byproduct. Layers were
separated, and the aqueous layer was extracted with Et2O
(3ꢃ10 mL). Aq HF (10%, 5 mL) was then added and the resulting
biphasic mixture was stirred rapidly for 30 min, the layers were
separated and the aqueous layer was extracted with diethyl ether
(3ꢃ10 mL). The combined ethereal layers were then washed with
water (20 mL), saturated aq NaHCO3, and brine (20 mL), and dried
over MgSO4. Filtration and solvent removal under reduced pres-
sure, followed by purification by column chromatography (20%
EtOAc/hexanes) gave 445 mg (73%) of the desired product as a clear
d
5.87 (ddd, J¼17.1, 10.2, 6.3 Hz, 1H), 5.25 (dt, J¼17.1, 1.2 Hz, 1H), 5.14
(dt, J¼10.2,1.2 Hz,1H), 4.21 (q, J¼7.2 Hz, 2H), 4.16e4.10 (m,1H), 2.38
(t, J¼6.1 Hz, 1H), 1.79e1.54 (m, 5H), 1.30 (t, J¼7.3 Hz, 3H). 13C NMR
(125.6 MHz, CDCl3)
d 153.8, 140.7, 115.1, 88.8, 73.5, 72.6, 61.8, 35.8,
23.4, 18.6, 14.0. HRMS (ESI-TOF) m/z [MþNa]þ calcd for C11H16O3Na
219.0997; found 219.0995.
4.5. Ethyl 2-(2-vinyl-3,4-dihydro-2H-pyran-6-yl)ethanoate (7b)
TBS-protected alcohol 5 (0.874 g, 2.82 mmol) was dissolved in
THF (5 mL), and TBAF (1.0 M, 2.82 mL, 2.82 mmol) was added to the
solution via syringe. The reaction mixture was allowed to stir at
room temperature overnight at which point the reaction was
judged to be complete by TLC. Solvent was then removed under
reduced pressure, and the crude residue was taken up in diethyl
ether (10 mL) and H2O (5 mL). The layers were separated, and the
aqueous layer was extracted with diethyl ether (3ꢃ10 mL). The
combined ether layers were washed with brine dried over anhy-
drous MgSO4. The solution was filtered and concentrated under
reduced pressure. The resulting oil was purified by silica column
(15% EtOAc/hexanes) to give 0.256 g of 7b (47%) as a pale yellow oil.
oil. 1H NMR (500 MHz, CDCl3)
d
5.84 (ddd, J¼17.1, 10.5, 6.1 Hz, 1H),
5.23 (ddd, J¼17.1, 1.5, 1.0 Hz, 1H), 5.13 (ddd, J¼10.5 Hz, 1.5, 1.0 Hz,
1H), 4.12 (q, J¼6.3 Hz,1H), 2.41 (t, J¼6.85 Hz, 2H),1.79e1.59 (m, 5H).
13C NMR (125.6 MHz, CDCl3)
d 140.5, 115.3, 105.2, 87.1, 72.4, 55.5,
35.5, 23.0, 18.8. HRMS (EI) m/z [MꢁH]þ calcd for C9H10N 148.0762;
found 148.0761.
4.8. 8-Oxo-3-cyclooctenecarbonitrile (11)
1H NMR (500 MHz, CDCl3)
d
5.89 (ddd, J¼17.3, 10.6, 5.6 Hz, 1H),
5.28 (app. d, J¼17.3 Hz,1H), 5.14 (app. d, J¼10.7 Hz,1H), 4.65 (app. t,
J¼3.5 Hz, 1H), 4.41e4.36 (m, 1H), 4.16 (q, J¼7.17 Hz, 2H), 3.04 (s,
2H), 2.15e2.06 (m, 1H), 2.06e1.98 (m, 1H), 1.91e1.84 (m, 1H),
1.69e1.60 (m, 1H), 1.26 (t, J¼7.2 Hz, 3H). 13C NMR (125.6 MHz,
Alcohol 10 (0.117 g, 0.783 mmol) was dissolved in DME (2 mL) in
a base-washed microwave vial. A solution of LHMDS (1.0 M,
0.0780 mL, 0.0780 mmol) was added via syringe and vial was
heated in a microwave reactor for 1 h at 210 ꢂC. Upon cooling,
solvent was removed under reduced pressure, and the resulting
crude product directly subjected to purification by column chro-
matography on silica gel (10% EtOAc/hexanes) to afford 93.2 mg
(80%) of the desired cyclooctenone product 11 as a pale yellow oil.
CDCl3)
d 170.6, 147.2, 137.6, 115.5, 98.9, 76.0, 60.7, 40.4, 27.0, 19.6,
14.2. HRMS (ESI-TOF) m/z [MþNa]þ calcd for C11H16O3Na 219.0997;
found 219.0996.
4.6. Ethyl 8-oxocyclooct-3-enecarboxylate (8), ethyl 3-(cyclo-
hex-3-enyl)-3-oxopropanoate (9)
1H NMR (500 MHz, CDCl3)
d 5.91e5.84 (m, 1H), 5.82e5.76 (m, 1H),
3.68e3.64 (m, 1H), 2.90e2.84 (m, 1H), 2.72e2.61 (m, 2H),
2.55e2.49 (m, 1H), 2.22e2.16 (m, 2H), 1.74e1.66 (m, 2H). 13C NMR
Ester 6 (58.0 mg, 0.296 mmol) was dissolved in phenetole
(1.5 mL) in a microwave vial and catalytic LHMDS (0.0296 mL,
0.0296 mmol) was added. The mixture was then heated with mi-
crowave irradiation at 210 ꢂC for 1 h. At this time, the reaction was
judged to be complete by TLC. The reaction mixture was directly
purified by column chromatography on silica gel (8% EtOAc/hex-
anes) to give 25.4 mg of rearranged product 821 (44%) and 8.50 mg
of 922 (15%), each as a pale yellow oil. Compound 8: 1H NMR
(125.6 MHz, CDCl3) d 203.1, 134.3, 125.8, 116.5, 48.0, 38.9, 26.2, 26.0,
24.0. HRMS (ESI-TOF) m/z [MþH]þ calcd for C9H12NO 150.0919;
found 150.0923.
4.9. 4-(5-Allyl-2,2-dimethyl-1,3-dioxan-5-yl)but-2-ynenitrile
(13)
To a ꢁ78 ꢂC solution of acetal 12 (1.68 g, 8.65 mmol) in an an-
hydrous diethyl ether (6 mL) was added n-BuLi (1.6 M in hexanes,
5.68 mL, 9.10 mmol) dropwise via syringe, and the resulting mix-
ture was allowed to stir for 15 min. A solution of phenyl cyanate
(dried over activated molecular sieves) in Et2O (6 mL) was then
added to the reaction mixture dropwise via cannula. The mixture
was allowed to stir at ꢁ78 ꢂC for 20 min before warming to room
temperature. The reaction was quenched with H2O (20 mL), the
layers were separated, and the aqueous layer was extracted with
diethyl ether (3ꢃ20 mL). The combined ethereal layers were then
washed with 10% NaOH (2ꢃ20 mL) to remove the phenol
(500 MHz, CDCl3)
d 5.79e5.67 (m, 2H), 4.24e4.11 (m, 2H),
3.49e3.43 (m, 1H), 2.91e2.83 (m, 1H), 2.72e2.65 (m, 1H),
2.53e2.46 (m, 1H), 2.41e2.34 (m, 1H), 2.27e2.17 (m, 1H), 2.17e2.09
(m, 1H), 1.78e1.69 (m, 1H), 1.61e1.51 (m, 1H), 1.25 (t, J¼7.1 Hz, 3H).
13C NMR (125.6 MHz, CDCl3)
d: 208.5, 169.4, 132.4, 127.8, 62.4, 61.3,
39.6, 26.5 25.0, 24.9, 14.1. Compound 9: 1H NMR (500 MHz, CDCl3)
d
: 5.69 (m, 2H), 4.19 (q, J¼7.1 Hz, 2H), 3.51 (s, 2H), 2.77e2.69 (m,
1H), 2.24e2.03 (m, 4H), 1.68e1.54 (m, 2H), 1.28 (t, J¼7.2 Hz, 3H). 13
C
NMR (125.6 MHz, CDCl3)
26.6, 24.6, 24.4, 14.1.
d: 205.4,167.3,126.7,125.0, 61.3, 47.4, 46.8,

A.W. Feldman et al. / Tetrahedron 70 (2014) 4147e4155
4153
byproduct. The organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The resulting crude residue
was purified by column chromatography (0%e17.5% EtOAc/hex-
anes) to give 1.64 g of nitrile 13 (86% yield) as a pale yellow oil. 1H
(d, J¼17.8 Hz, 1H), 2.37e2.24 (m, 4H), 1.90 (quin, J¼7.3 Hz, 2H), 1.72
(br s, 1H), 1.56e1.46 (m, 2H), 1.42 (s, 3H), 1.39 (s, 3H). 13C NMR
(125.6 MHz, CDCl3)
d 147.3, 125.6, 105.1, 98.4, 85.4, 67.7, 67.6, 66.5,
57.3, 38.4, 36.1, 32.1, 31.3, 27.5, 23.3, 23.1, 19.9. HRMS (ESI-TOF) m/z
NMR (500 MHz, CDCl3) d: 5.72e5.63 (m, 1H), 5.20e5.14 (m, 2H),
[MþH]þ calcd for C17H24NO3 290.1756; found 290.1755.
3.72 (d, J¼12.2 Hz, 2H), 3.54 (d, J¼¼12.2 Hz, 2H), 2.68 (s, 2H), 2.08
(d, J¼7.3 Hz, 2H), 1.42 (s, 3H), 1.40 (s, 3H). 13C NMR (125.6 MHz,
4.12. 2-Methyl-1-octen-7-yn-3-ol
CDCl3) d: 130.7, 120.1, 105.1, 98.5, 84.8, 66.6 (two signals), 57.5, 37.1,
36.5, 27.7, 22.7, 19.6. HRMS (ESI-TOF) m/z [MþH]þ calcd for
In a dry round bottom flask, 2-bromopropene (0.735 g,
C
13H18NO2 220.1338; found 220.1340.
6.07 mmol) was dissolved in 15 mL anhydrous diethyl ether and
cooled to ꢁ78 ꢂC. A solution of t-BuLi (1.7 M, 7.14 mL, 12.1 mmol)
was then added dropwise via a syringe. The resulting mixture was
allowed to stir at ꢁ78 ꢂC for 15 min before warming to 0 ꢂC for
another 15 min to destroy any excess t-BuLi. At this point, the so-
lution was cooled to ꢁ78 ꢂC and a solution of 6-(trimethylsilyl)-5-
hexynal29 (0.341 g, 2.02 mmol) in 3 mL diethyl ether was added
to the reaction mixture dropwise via cannula. After 20 min of
stirring at this temperature, the reaction was quenched with sat-
urated NH4Cl (2 mL) and allowed to warm to room temperature.
Distilled water (5 mL) was then added to the mixture and the layers
were separated. The aqueous layer was extracted with diethyl ether
(3ꢃ10 mL), the combined ethereal layers were washed with brine,
and dried over MgSO4. The solution was then filtered and con-
centrated under reduced pressure. The resulting crude residue was
then dissolved in THF (4 mL) and catalytic TBAF (1.0M, 0.200 mL,
0.200 mmol) was added via syringe. Upon stirring at room tem-
perature for 15 min, solvent was removed under reduced pressure
and the residue was taken up in diethyl ether (10 mL) and H2O
(5 mL). The layers were separated, and the aqueous layer was
washed with diethyl ether (3ꢃ10 mL). The combined ethereal
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification of the crude oil by column chroma-
tography on silica gel (8.5% ethyl acetate in hexanes) gave 0.211 g of
the desired allylic alcohol (75% yield) as a pale yellow oil. 1H NMR
4.10. 4-(2,2-Dimethyl-5-(2-oxoethyl)-1,3-dioxan-5-yl)but-2-
ynenitrile (14)
Nitrile 13 (1.41 g, 6.45 mmol) was dissolved in aq acetone
(50 mL, 9:1 acetone to water) along with OsO4 (4% in water,
1.2 mL) and NMO (0.982 g, 8.36 mmol). The reaction mixture was
allowed to stir at room temperature for 6 h before quenching with
saturated thiosulfate solution. The mixture was then extracted
with DCM (3ꢃ20 mL) and the combined organic layers were
washed with brine and dried over anhydrous MgSO4. The solution
was filtered and concentrated to give the crude diol, which was
used without purification for the next step. To a rapidly stirred
mixture of silica gel (8 g) in DCM (65 mL) was added NaIO4
(0.65 M in H2O, 13.0 mL, 8.44 mmol) followed by the crude diol
prepared above in 10 mL DCM. The reaction was judged to be
complete by TLC after 10 min, at which point the solution was
vacuum filtered and the solids were washed with more DCM. The
filtrate was concentrated and the resulting residue was taken up
in diethyl ether (50 mL) and H2O (20 mL). The aqueous layer was
separated and extracted with diethyl ether (3ꢃ20 mL). The com-
bined ethereal layers were washed with brine and dried over
anhydrous MgSO4. The solution was filtered and concentrated
under reduced pressure, and resulting crude oil was purified by
combiflash column chromatography (0e26% gradient of ethyl
acetate in hexanes) to give 0.923 g of aldehyde 14 (65% yield over
(500 MHz, CDCl3)
d 4.95e4.94 (m, 1H), 4.84e4.83 (m, 1H), 4.09
(app. t, J¼6.1 Hz, 1H), 2.25e2.20 (m, 2H), 1.95 (t, J¼2.7 Hz, 1H), 1.73
two steps). 1H NMR (500 MHz, CDCl3)
J¼12.2 Hz, 2H), 3.71 (d, J¼12.2 Hz, 2H), 2.87 (s, 2H), 2.63 (s, 2H),
1.43 (s, 3H), 1.41 (s, 3H). 13C NMR (125.6 MHz, CDCl3)
199.1, 104.8,
d
9.80 (s, 1H), 3.78 (d,
(s, 3H), 1.72e1.42 (m, 5H). 13C NMR (125.6 MHz, CDCl3)
d 147.4, 111.1,
84.2, 75.4, 68.5, 33.8, 24.5, 18.3, 17.5. HRMS (EI) m/z [MꢁH]þ calcd
d
for C9H13O 137.0966; found 137.0967.
98.7, 83.7, 66.1 (two signals), 57.9, 45.6, 35.9, 25.3, 22.7, 21.8.
HRMS (ESI-TOF) m/z [MþH]þ calcd for C12H16NO3 222.1130; found
222.1129.
4.13. 7-Hydroxy-8-methyl-8-nonen-2-ynenitrile (16)
The title compound was prepared from 2-methyl-1-octen-7-
yn-3-ol in 76% yield according to the general procedure de-
4.11. 4-(5-(2-Cyclopentenyl-2-hydroxyethyl)-2,2-dimethyl-
1,3-dioxan-5-yl)but-2-ynenitrile (15)
scribed for the preparation of 10. 1H NMR (500 MHz, CDCl3)
d:
4.97e4.95 (m, 1H), 4.87 (app. t, J¼1.5 Hz, 1H), 4.08 (t, J¼5.6 Hz, 1H),
1-Iodocyclopentene (280 mg, 1.45 mmol) was dissolved in an-
hydrous diethyl ether (4 mL) and cooled to ꢁ78 ꢂC. A solution of t-
BuLi (1.7 M, 1.70 mL, 2.90 mmol) was then added dropwise via
syringe. The resulting mixture was allowed to stir at ꢁ78 ꢂC for
10 min before warming to 0 ꢂC for an additional 30 min. The
resulting vinyllithium solution was then added dropwise to alde-
hyde 14 (320 mg, 1.45 mmol) in diethyl ether (6.0 mL) at ꢁ78Cꢂ
over 30 min and the resulting mixture was allowed to stir at this
temperature for another 30 min before quenching with methanol
(0.5 mL). Upon warming, H2O (10 mL) was added, as well as addi-
tional diethyl ether (20 mL). Layers were separated, and the
aqueous layer was extracted with Et2O (3ꢃ10 mL). The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
resulting crude oil was purified via column chromatography on
silica gel (49% hexanes, 49% DCM, 2% ethyl acetate) to give 220 mg
of the desired allylic alcohol 15 (52%) as a pale yellow oil. 1H NMR
2.43e2.39 (m, 2H), 1.73 (s, 3H), 1.72e1.53 (m, 5H). 13C NMR
(125.6 MHz, CDCl3) d: 147.0, 111.4, 105.2, 87.0, 75.1, 55.5, 33.5, 23.3,
18.8, 17.6. HRMS (ESI-TOF) m/z [MþH]þ calcd for C10H14NO
164.1075; found 164.1079.
4.14. 3-Methyl-8-oxo-3-cyclooctenecarbonitrile (17)
The title compound was prepared from 16 in 75% yield
according the general procedure described for the preparation of
11. 1H NMR (500 MHz, CDCl3)
d
5.55 (app td, J¼8.33, 1.4 Hz, 1H),
3.65e3.61 (m, 1H), 2.84e2.78 (m, 1H), 2.76e2.69 (m, 2H),
2.48e2.42 (m, 1H), 2.18e2.05 (m, 2H), 1.85 (s, 3H), 1.78e1.63 (m,
2H). 13C NMR (125.6 MHz, CDCl3)
d 202.8, 133.8, 128.2, 117.0, 46.6,
39.1, 30.7, 27.1, 25.2, 23.8. HRMS (ESI-TOF) m/z [MþH]þ calcd for
C10H14NO 164.1075; found 164.1077.
4.15. 1-(1-Cyclopentenyl)-5-hexyn-1-ol
(500 MHz, CDCl3)
3.80 (d, J¼12.0 Hz, 1H), 3.76 (d, J¼12.0 Hz, 1H), 3.75 (dd, J¼11.8,
2.2 Hz, 1H), 3.58 (dd, 12.0, 2.2 Hz, 1H), 3.00 (d, J¼17.8 Hz, 1H), 2.71
d
5.63e5.60 (m, 1H), 4.42 (dd, J¼8.3, 2.4 Hz, 1H),
The title compound was prepared from 1-iodocyclopentene and
6-(trimethylsilyl)-5-hexynal in 65% yield according to the general

4154
A.W. Feldman et al. / Tetrahedron 70 (2014) 4147e4155
procedure described for the preparation of 2-methyl-1-octen-7-yn-
3-ol. 1H NMR (500 MHz, CDCl3)
5.57e5.59 (m, 1H), 4.26 (t,
4.20. 4-(5-(2-Hydroxy-3-methylbut-3-en-1-yl)-2,2-dimethyl-
1,3-dioxan-5-yl)but-2-ynenitrile (22)
d
J¼6.2 Hz, 1H), 2.20e2.34 (overlapping patterns, 4H), 2.21 (td, J¼6.7,
2.5 Hz, 2H),1.93 (t, J¼2.7 Hz,1H),1.87 (quin, J¼7.4 Hz, 2H),1.56e1.74
The title compound was prepared in 46% yield from 14 and 2-
(m, 3H), 1.47e1.56 (m, 2H). 13C NMR (125.6 MHz, CDCl3)
d
146.9,
bromopropene according to the general procedure described for
125.6, 84.3, 70.8, 68.5, 34.4, 32.1, 31.0, 24.5, 23.3, 18.3. HRMS (ESI-
the preparation 15. 1H NMR (500 MHz, CDCl3)
d: 4.99 (s, 1H), 4.85 (t,
TOF) m/z [MþH]þ calcd for C11H17NO 165.1279; found 165.1283.
J¼1.5 Hz, 1H), 4.22 (dd, J¼9.8, 3.0 Hz, 1H), 3.81 (d, J¼12.0 Hz, 1H),
3.77 (dd, J¼11.9, 2.0 Hz,1H), 3.75 (d, J¼12.0 Hz,1H), 3.60 (dd, J¼11.9,
2.0 Hz, 1H), 3.04 (d, J¼17.6 Hz, 1H), 2.79 (d, J¼17.6 Hz, 1H), 1.83 (br s,
1H),1.74 (s, 3H),1.43e1.52 (m, 2H),1.42 (s, 3H),1.39 (s, 3H). 13C NMR
4.16. 7-(1-Cyclopentenyl)-7-hydroxyhept-2-ynenitrile (18)
(125.6 MHz, CDCl3)
d 148.0, 110.9, 105.1, 98.4, 85.3, 72.0, 67.8, 66.4,
The title compound was prepared from 1-(1-cyclopentenyl)-5-
hexyn-1-ol in 65% yield according to the general procedure de-
scribed for the preparation of 10. 1H NMR (500 MHz, CDCl3)
57.4, 38.2, 36.1, 27.4, 23.0, 19.9, 17.9. HRMS (ESI-TOF) m/z [MþH]þ
calcd for C15H22NO3 264.1600; found 264.1604.
d
5.59e5.61 (m, 1H), 4.20e4.27 (m, 1H), 2.39 (app. t, J¼6.9 Hz, 2H),
4.21. 3,3,11-Trimethyl-8-oxo-2,4-dioxaspiro[5.7]tridec-11-
ene-9-carbonitrile (23)
2.22e2.35 (overlapping patterns, 4H), 1.89 (quin, J¼7.6 Hz, 2H),
1.65e1.75 (m, 2H), 1.59e1.16 (m, 2H), 1.57 (br s, 1H). 13C NMR
(125.6 MHz, CDCl3)
d 146.5, 125.9, 105.2, 87.2, 70.5, 55.5, 34.1, 32.1,
31.1, 23.3, 23.2, 18.8. HRMS (ESI-TOF) m/z [MþNa]þ calcd for
The title compound was prepared in 84% yield from 22
according the general procedure described for the preparation of
C
12H15NONa 212.1051; found 212.1050.
11. 1H NMR (500 MHz, CDCl3)
d
5.54 (app. t, J¼8.3 Hz,1H), 3.66e3.71
(m, 2H), 3.55e3.62 (m, 3H), 2.69 (d, J¼12.3 Hz, 1H), 2.43 (d,
4.17. Bicyclic cyano ketone 19
J¼12.3 Hz,1H), 2.68e2.72 (m, 2H), 2.08e2.16 (m, 1H), 1.98e2.08 (m,
1H), 1.98 (s, 3H), 1.40 (s, 6H). 13C NMR (125.6 MHz, CDCl3)
d: 200.6,
The title compound was prepared from 18 as a 2.7:1 mixture of
diastereomers in 64% yield according to the general procedure
described for the preparation of 11. Major diastereomer: 1H NMR
135.6, 124.3, 116.8, 98.5, 67.5, 67.1, 46.5, 43.0, 37.2, 36.6, 31.5, 31.2,
23.9, 23.4. HRMS (ESI-TOF) m/z [MꢁCH3]þ calcd for C14H18NO3
248.1287; found 248.1284.
(500 MHz, CDCl3)
d
5.59 (app. t, J¼8.3 Hz, 1H), 3.36 (d, J¼11.7 Hz,
1H), 3.06e3.50 (m, 1H), 2.54 (app. t, J¼6.6 Hz, 2H), 2.24e2.41 (m,
2H), 2.14e2.20 (m, 2H), 1.82e1.92 (m, 2H), 1.66e1.74 (m, 2H),
4.22. Bicyclic cyano ketone 24
1.42e1.50 (m, 2H). 13C NMR (125.6 MHz, CDCl3)
d 203.4, 144.0,
The title compound was prepared in 78% yield as a 1:1 mixture
of diastereomers according the general procedure described for the
preparation of 11. Major diastereomer (after purification by col-
122.8, 117.5, 116.6, 52.7, 40.7, 39.0, 32.4, 32.2, 27.4, 23.3. HRMS (ESI-
TOF) m/z [MþH]þ calcd for C12H16NO 190.1232; found 190.1232.
umn): 1H NMR (500 MHz, CDCl3)
d
5.62 (app. t, J¼7.8 Hz, 1H), 3.91
4.18. 4-(5-(2-Hydroxy-3-butenyl)-2,2-dimethyl-1,3-dioxan-5-
yl)but-2-ynenitrile (20)
(d, J¼11.7 Hz, 1H), 3.61 (d, J¼11.7 Hz, 1H), 3.51 (d, J¼11.7 Hz, 1H),
3.43 (d, J¼11.8 Hz, 1H), 3.20e3.00 (m, 1H), 2.61 (d, J¼12.4 Hz, 1H),
2.39 (d, J¼12.4 Hz, 1H), 2.42e2.25 (m, 2H), 2.19e2.10 (m, 1H),
1.92e1.83 (m, 1H), 1.80e1.72 (m, 1H), 1.69e1.62 (m, 3H), 1.56e1.51
Aldehyde 14 (0.230 g, 1.04 mmol) was dissolved diethyl ether
(6 mL) and cooled to ꢁ78 ꢂC, and vinyl magnesium chloride (1.6 M,
0.650 ml, 1.04 mmol) was added dropwise. The reaction mixture
was allowed to stir for 2 h at ꢁ78 ꢂC before being quenched with
methanol (0.1 mL). Upon warming to room temperature, 0.5 mL of
saturated K2CO3 was added, the resulting precipitate was filtered,
and the filtrate was concentrated under vacuum. The resulting
crude product was purified by column chromatography on silica gel
(20% EtOAc/hexanes) to give 192 mg (74%) of the desired nitrile 20
(m, 1H), 1.41 (s, 6H). 13C NMR (125.6 MHz, CDCl3)
d 201.4, 145.9,
119.7, 116.3, 98.4, 67.6, 67.1, 53.2, 40.8, 36.4, 35.3, 33.1, 32.2, 31.7,
24.6, 23.9, 23.7. HRMS (ESI-TOF) m/z [MþH]þ calcd for C17H24NO3
290.1756; found 290.1755.
4.23. Endocyclic dihydropyran (12b), (E)-exocyclic tetrahy-
dropyran (12a)
as a pale yellow oil. 1H NMR (500 MHz, CDCl3)
d: 5.91e5.84 (ddd,
Nitrile 10 (75.5 mg, 0.506 mmol) was dissolved in DME (2.0 mL),
J¼17.1,10.2, 5.8 Hz,1H), 5.25 (dt, J¼17.10,1.2 Hz,1H), 5.13 (dt, J¼10.2,
1.2 Hz, 1H), 4.32 (app. q, J¼5.8 Hz, 1H), 3.82e3.74 (overlapping
patterns, 3H), 3.60 (dd, J¼11.7, 1.9 Hz, 1H), 2.99 (d, J¼17.8 Hz, 1H),
2.72 (d, J¼17.8 Hz,1H),1.71 (br s,1H), 1.50e1.48 (m, 2H),1.42 (s, 3H),
and
a catalytic amount of LHMDS (1.0 M in THF, 50 mL,
0.0500 mmol) was added. The reaction mixture was allowed to stir
at room temperature for 4 h. The solvents were removed and the
residue was subjected to purification by column chromatography
on silica gel (8% EtOAc/hexanes) to give 20.6 mg of 12a (27%) and
41.3 mg of 12b (55%). Compound 12a: 1H NMR (500 MHz, CDCl3)
1.40 (s, 3H). 13C NMR (125.6 MHz, CDCl3)
d 141.1, 115.1, 105.1, 98.4,
85.2, 69.6, 67.7, 66.5, 66.1, 39.7, 36.1, 27.2, 23.2, 20.1. HRMS (ESI-TOF)
m/z [MþH]þ calcd for C14H20NO3 250.1443; found 250.1452.
d
5.87 (ddd, J¼17.6,10.7, 5.4 Hz,1H), 5.37 (dt, J¼17.6,1.5 Hz,1H), 5.23
(dt, J¼10.7, 1.5 Hz, 1H), 4.52e4.56 (m, 1H), 4.33 (t, J¼1.0 Hz, 1H),
2.37e2.43 (m, 1H), 2.28e2.34 (m, 1H), 1.91e1.97 (m, 1H), 1.78e1.86
(m, 1H), 1.71e1.78 (m, 1H), 1.62e1.71 (m, 1H). 13C NMR (125.6 MHz,
4.19. 3,3-Dimethyl-8-oxo-2,4-dioxaspiro[5.7]tridec-11-ene-9-
carbonitrile (21)
CDCl3)
d 173.1, 136.2, 116.8, 116.3, 78.9, 73.8, 28.6, 27.7, 18.5. HRMS
The title compound was prepared in 79% yield from 19
(ESI-TOF) m/z [MþH]þ calcd for C9H12N 150.0919; found 150.0917.
according the general procedure described for the preparation of
Compound 12b: 1H NMR (500 MHz, CDCl3)
10.7 Hz, 5.4 Hz, 1H), 5.29 (dt, J¼17.1, 1.5 Hz, 1H), 5.19 (dt, J¼10.7,
1.5 Hz, 1H), 4.85e4.88 (m, 1H), 4.36e4.41 (m, 1H), 3.09 (s, 2H),
1.99e2.14 (m, 2H), 1.86e1.92 (m, 1H), 1.59e1.67 (m, 1H). 13C NMR
d
5.87 (ddd, J¼17.6,
11. 1H NMR (500 MHz, CDCl3)
d
6.01e5.94 (m, 1H), 5.93e5.86 (m,
1H), 3.76e3.70 (m, 2H), 3.66e3.58 (m, 3H), 2.78e2.66 (m, 3H), 2.47
(d, J¼12.7 Hz, 1H), 2.28e2.24 (m, 1H), 2.15e2.08 (m, 1H), 1.43 (s,
6H). 13C NMR (125.6 MHz, CDCl3)
d
200.9, 131.2, 127.4, 116.5, 98.5,
(125.6 MHz, CDCl3) d: 143.4,136.9,116.4,116.0, 98.9, 76.5, 26.8, 23.0,
67.5, 67.2, 47.7, 42.9, 36.4, 30.5, 26.4, 24.1, 23.3. HRMS (ESI-TOF) m/z
19.5. HRMS (ESI-TOF) m/z [MþH]þ calcd for C9H12N 150.0919;
[MþH]þ calcd for C14H20NO3 250.1443; found 250.1442.
found 150.0917.

A.W. Feldman et al. / Tetrahedron 70 (2014) 4147e4155
4155
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Acknowledgements
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This research was partially supported by grant from the National
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