Tandem Blaise/retro-Blaise reaction for the nitrile-mediated regioselective intermolecular addition of unstabilized zinc ester enolates (Reformatsky Reagents) to 1-alkynes and 1,3-enynes

Article abstract of DOI:10.1021/jo402015n

We report the novel use of a nitrile as a mediator to achieve the regioselective intermolecular addition of unstabilized zinc ester enolates (Reformatsky reagents) to 1-alkynes and 1,3-enynes. This reaction is made possible by a reversible addition of enolates to a nitrile (Blaise reaction), generating a zinc aza-enolate that, unlike zinc ester enolates, can add intermolecularly to 1-alkynes and 1,3-enynes. Subsequent removal of the nitrile through a retro-Blaise reaction generates the targeted addition product. This method is combined with a Diels-Alder reaction and subsequent oxidative aromatization, providing a tandem one-pot de novo construction of α-arylated alkanoates from Reformatsky reagents.

Full text of DOI:10.1021/jo402015n

Article
pubs.acs.org/joc
Tandem Blaise/retro-Blaise Reaction for the Nitrile-Mediated
Regioselective Intermolecular Addition of Unstabilized Zinc Ester
Enolates (Reformatsky Reagents) to 1‑Alkynes and 1,3-Enynes
Ju Hyun Kim, Yu Sung Chun, and Sang-gi Lee*
Department of Chemistry and Nano Science, Ewha Womans University, 120-750 Seoul, Korea
S
* Supporting Information
ABSTRACT: We report the novel use of a nitrile as a
mediator to achieve the regioselective intermolecular addition
of unstabilized zinc ester enolates (Reformatsky reagents) to 1-
alkynes and 1,3-enynes. This reaction is made possible by a
reversible addition of enolates to a nitrile (Blaise reaction),
generating a zinc aza-enolate that, unlike zinc ester enolates,
can add intermolecularly to 1-alkynes and 1,3-enynes.
Subsequent removal of the nitrile through a retro-Blaise
reaction generates the targeted addition product. This method
is combined with a Diels−Alder reaction and subsequent
oxidative aromatization, providing a tandem one-pot de novo
construction of α-arylated alkanoates from Reformatsky reagents.
Scheme 1. Tandem Blaise/Vinylation/retro-Blaise Reactions
for the Nitrile-Mediated Intermolecular Addition of
Unstabilized Zinc Ester Enolates to 1-Alkynes
INTRODUCTION
■
The addition of enolate nucleophiles to nonactivated carbon−
carbon multiple bonds is a synthetically highly challenging and
important reaction for carbon−carbon bond formations. During
recent decades, significant advances have been made in the
addition of metal enolates to unactivated alkenes and alkynes.1
However, the intermolecular addition of the unstabilized
enolates to 1-alkynes is inherently difficult to achieve because
the enolate anion is basic enough to deprotonate the acidic
terminal Csp−H (for example, CH3CO2Et pKa = 29.52a and
PhCCH pKa = 28.8 in DMSO).2b All reported intermolecular
additions of enolates to 1-alkynes to date have been restricted to
stabilized enolates formed in situ from a metal catalyst or
mediator (i.e., Zn,3 In,4 Mn,5 Re,6 and Ir7) with 1,3-dicarbonyl
derivatives. Alternative methods to address this limitation were
developed, including the addition to nonactivated 1-alkynes of
silyl enol ethers of ketones, promoted by stoichiometric or excess
amounts of GaCl38 or SnCl4,9 or of ketene silyl acetals using one
equiv of InCl3.10 However, these approaches required not only
the preparation and isolation of silyl enolates as a separate step
but also expensive or harmful metallic Lewis acids as mediators.
The strategy described in this article is the use of an organic
nitrile as a reversible mediator to accomplish the regioselective
intermolecular addition of unstabilized zinc ester enolates
(Reformatsky reagents) to 1-alkynes (Scheme 1).
Blaise reaction intermediate A that combines an ambivalent C-/
N-nucleophilic enamine moiety with an electrophilic ester group,
permitting possible tandem reaction with electrophiles,
nucleophiles, or both. During the course of our studies on the
use of the intermediate A in tandem schemes,13 we envisioned
that A could be considered as an isoelectronic variant of the zinc
complexes of β-ketoesters that enable intermolecular addition to
1-alkynes 2.3 In a previous communication, we have reported
that the α-unsubstituted intermediate A (R1 = H) has a
propensity to be a C-nucleophile and to react with 1-alkynes
The addition of a Reformatsky reagent to a nitrile, known as
the Blaise reaction,11 proceeds via the zinc bromide complex of β-
enaminoester intermediate A, which affords a β-ketoester or β-
enaminoester after hydrolytic workup under acidic or basic
conditions, respectively.12 However, there is no report on the
tandem use of the intermediate A as a functionalized organozinc
reagent to date. Recently, we recognized the unique features of
Received: September 13, 2013
Published: October 15, 2013
© 2013 American Chemical Society
11483
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
chemoselectively at the α-carbon to afford α-vinylated β-
enaminoesters 3 in high yield.13c A mechanistic study suggested
the formation of zinc complex B as a second intermediate, which
may rapidly tautomerize to more stable conjugated enamine
complex C, affording enaminoester 3 after hydrolytic workup.
On the basis of these observations, we anticipated that
intermediate B could also possibly undergo a retro-Blaise
fragmentation, excising a nitrile moiety to generate the zinc
dienolate D. In this tandem Blaise/vinylation/retro-Blaise
reaction sequence, the nitrile plays the role of a reversible
mediator14 for the Reformatsky reagent 1, making possible an
intermolecular addition to 1-alkynes that is impossible to
conduct directly with 1.15 Herein, we report the successful
development of the nitrile-mediated tandem intermolecular
addition of unstabilized zinc ester enolates (Reformatsky
reagents) to 1-alkynes and 1,3-enynes through a Blaise/
vinylation/retro-Blaise reaction sequence. To the best of our
knowledge, this represents the first example of retro-Blaise
reaction.
Reformatsky reagent 1a, generated in situ from ethyl α-
bromopropionate and zinc, was reacted with benzonitrile to
form the α-methyl-substituted intermediate A (R = Ph and R1 =
Me). Tandem reaction of A (R = Ph and R1 = Me) with 1.3 equiv
of phenylacetylene (2a) in refluxing THF for 24 h resulted in an
89:11 mixture of 4a and (E)-5a16 in 56% yield (entry 1, Table 1).
This result clearly indicated that, in sharp contrast to the reaction
with nitriles,13l the α-substituted intermediate A could act as a
carbon nucleophile toward 1-alkynes and that the expected retro-
Blaise reaction occurred under the reaction conditions, possibly
as the result of the steric interactions between R and R1 in
intermediate B. After screening different nitriles (entries 2−4,
Table 1), we chose 3-phenylpropionitrile as a standard nitrile,
which affords a mixture of 4a and 5a in 71% yield (entry 4, Table
1). Careful monitoring of the reactions by TLC and GC
indicated that the vinylation reaction of A to form intermediate B
and the retro-Blaise reaction proceeded at comparable rates and
thus that the generated zinc dienolate D could deprotonate
alkyne 2a, affording 4a and 5a prior to workup (see Scheme 4 for
a detailed mechanism). Gratifyingly, when the same tandem
reaction was carried out with 2.1 equiv of phenylacetylene 2a, the
yield increased to 88% while conserving a 4a/5a ratio of 89:11
(entry 5, Table 1). The reaction is quite clean, allowing for an
easy separation of the reaction products from the regenerated
nitrile by simple silica column chromatography. However, at
room temperature, neither the vinylation reaction nor the retro-
Blaise reaction proceed efficiently; after 3 days, the ethyl 2-
methyl-3-oxo-5-phenyl-2-(1-phenylethenyl)pentanoate (6) can
be isolated in only 26% yield (entry 6, Table 1), supporting the
formation of intermediate B.
We next investigated the generality of this nitrile-mediated
intermolecular addition of Reformatsky reagents to 1-alkynes. As
shown in Table 2, the established reaction conditions proved to
be generally effective for phenylalkynes bearing electron-
donating methyl (2b and 2c) and methoxy substituents (2d)
and afforded the corresponding 4b−d as major isomers in good
yields (entries 2−4, Table 2). The reactions with halogenated
phenylacetylenes (2e−g) also proceeded efficiently to afford
4e−g in good yields (entries 5−7, Table 2). The nitrile (2h) and
ester groups (2j) were tolerated under these reaction conditions
and resulted in the α-vinylated 4h (entry 8, Table 2) and 4j
(entry 10, Table 2) with high selectivities, albeit at the expense of
slightly decreased yields. The aliphatic alkyne 2i was less reactive
toward the intermediate A, and required higher reaction
temperatures (100 °C in 1,4-dioxane) for a successful vinylation,
but the retro-Blaise reaction occurred rapidly to afford the
corresponding addition products 4i and 5i (4i/5i = 83:17) in
moderate yields (entry 9, Table 2). Unactivated internal alkynes,
such as 1-phenylprop-1-yne, do not participate in the vinylation
reaction. Reformatsky reagents bearing a methyl ester (1b) or n-
propyl group at R1 (1c) did not significantly diminish the
reaction efficiency and resulted in the corresponding 4k and 4l as
major isomers in good yields (entries 11 and 12, Table 2). As we
observed previously,13c the α-unsubstituted intermediate A
formed from Reformatsky reagent (R1 = H) (1d) undergoes
vinylation with phenylacetylene 2a efficiently in refluxing THF.
However, the retro-Blaise reaction did not occur at this
temperature, which could be ascribed to the tautomerization of
B (Scheme 1) to the more thermodynamically stable enamine
complex C. The complete sequence requires higher temper-
atures (120 °C in DMF) to afford a mixture of 4m and 5m in 57%
yield (entry 13, Table 2). In this case, the thermodynamically
more stable 5m was formed as the predominant product with
RESULTS AND DISCUSSION
■
Our previous studies on the chemoselective electrophilic
trapping of the Blaise reaction intermediate A with various
electrophiles suggested that the C-/N-chemoselectivity of A is
largely determined by the α-subtituent R1. The α-unsubstituted
A (R1 = H) generally showed propensity to be a C-
nucleophile,13a−h whereas the α-substituted A (R1 ≠ H) showed
N-nucleophilic nature,13i,l,m for example, reacting with nitrile
electrophiles at the nitrogen atom to afford pyrimidin-2-ones.13l
Therefore, the success of the nitrile-mediated strategy shown in
Scheme 1 would largely be determined by the C-/N-chemo-
selectivity of the α-substituted intermediate A (R1 ≠ H) toward
1-alkynes. To determine this outcome, we first investigated the
reactivity and C-/N-chemoselectivity of the α-methyl-substi-
tuted intermediate A (R1 = Me) toward 1-alkynes (Table 1). The
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
RCN
PhCN
2a (equiv)
yield (%)
4a/5a
1
2
3
4
5
1.3
1.3
1.3
1.3
2.1
2.1
56
66
53
71
88
26
89/11
89/11
88/12
89/11
89/11
6
PhCH2CN
(CH3)2CHCN
PhCH2CH2CN
PhCH2CH2CN
PhCH2CH2CN
d
6
a
The reaction conditions are as follows. The Reformatsky reagent 1a,
generated in situ from ethyl α-bromopropionate (2.6 mmol) and zinc
(4.0 mmol), was reacted with RCN (2.0 mmol) in THF (0.6 mL). A
solution of 2a in THF (0.6 mL) was added after full conversion of the
b
nitrile to intermediate A (>95% by GC). Isolated yield (4a + 5a) (the
nitrile was used as a limiting reagent to maximize the formation of A,
and the yield was calculated on the basis of the limiting reagent).
c
d
1
Determined by H NMR analysis. The reaction was carried out at
room temperature for 3 days.
11484
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
a
Table 2. Nitrile-Mediated Intermolecular Addition of Reformatsky Reagent to 1-Alkynes
a
The reaction conditions were as follows. The Reformatsky reagent 1, generated in situ from alkyl bromoalkanoate (2.6 mmol) and Zn (4.0 mmol),
was reacted with 3-phenylpropionitrile (2.0 mmol) in THF (0.6 mL). A solution of 2 (4.2 mmol) in THF (0.6 mL) was added after full conversion
b
of the nitrile to intermediate A (>95% by GC). The ratio of 4/5 was determined either by 1H NMR analysis of crude product or from the isolated
c
yields of 4 and 5. Isolated yields (4 + 5) (the nitrile was used as a limiting reagent to maximize the formation of A, and the yield was calculated
d
e
based on the limiting reagent). The reaction was carried out at 100 °C in 1,4-dioxane. The reaction was carried out at 120 °C in DMF.
11485
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
ratio of 4m/5m = 5:95. It is interesting to note that all γ-
protonated products (E)-5 were formed stereoselectively with
the R3 and ester groups in trans position, implying stereoselective
γ-protonation of zinc dienolate D. By contrast, the tandem
reaction of intermediate A, formed with the Reformatsky reagent
1e, generated in situ from α-bromo-γ-lactone, with 2a resulted in
a 1:1 mixture of (E/Z)-α-alkenylidenated γ-lactone 5n in 72%
yield.
This nitrile-mediated tandem addition reaction can be
extended to 1,3-enynes, where the reaction pathways can be
determined by the α-substituents. Previously, we observed that
the tandem reaction of α-unsubstituted Blaise reaction
intermediate A (R1 = H) with acyclic and cyclic 1,3-enynes in
1,4-dioxane at 100 °C afforded the corresponding pyridine
derivatives 7 in high yields (Scheme 2).13g In contrast, the
methyl groups in 4a and 5a, respectively, is consistent with the
generation of unlabeled 2a during the reaction.
On the basis of these deuterium-labeling experiments and our
previous results on the formation of α-vinylated β-enaminoesters
313c and pyridine derivatives 7,13g the plausible reaction pathways
of the tandem reactions of A with 1-alkynes and 1,3-enynes are
summarized in Scheme 4. The Blaise reaction intermediate A acts
as a C-nucleophile and reacted with alkyne 2 regioselectively to
form vinylzinc bromide E, which abstracted the proton from the
second alkyne 2, resulting in zinc acetylide 2-ZnBr and F. The
inter- and/or intramolecular deprotonation of the N−H proton
by 2-ZnBr could afford the vinylated zinc bromide complex B,
regenerating starting alkyne 2. In this manner, even a reaction
with deuterium-labeled 2-d can generate the unlabeled 2-H,
which is involved in the reaction cycles explaining the observed
proton and deuterium scrambling from the reaction shown in
Scheme 3b. The reaction pathways of intermediate B are largely
determined by the α-substituent R1. When R1 = H, B is in
equilibrium with its fully conjugated tautomeric forms C or C′.
Whereas C affords the α-vinylated β-enaminoester 3 after
workup,13c at high reaction temperature the minor tautomer B
(R1 = H) underwent the retro-Blaise reaction to afford D,
producing 5m (entry 13, Table 2). The intermediate C′ could
irreversibly isomerize to the N-zincated 1-azatriene G, which
undergoes a 6π−electrocyclization and/or cycloaddition to form
the pyridine ring after elimination of HZnBr.13g In contrast, for
the intermediate B (R1 ≠ H), formed by reaction of α-substituted
intermediate A (R1 ≠ H), tautomerization is not feasible. Instead,
the retro-Blaise reaction pathway dominates, driven by the
relaxation of the steric strain imposed by the interactions
between R, R1, and R3. The α-vinylated zinc enolate D thus
generated may be in equilibrium with the α-C-bound ZnBr D-1
and γ-C-bound ZnBr D-2, which upon protonation by starting
alkyne 2 leads to 4 and trans-5, respectively, and the zincated
alkyne 2-ZnBr. The formation of 2-ZnBr at this stage constitutes
an unproductive sink for the alkyne, justifying the need for an
excess of this reagent to achieve full conversion to 4 and 5.
Finally, the success of the nitrile-assisted α-dienylation
provides, in combination with Diels−Alder and oxidative
aromatization, a new tandem one-pot route for the de novo
construction of α-arylated alkanoates from Reformatsky reagents
(Scheme 5).17 The α-dienylated product 4o is more reactive than
the pentasubstituted diene 5o. Consequently, diene 4o can be
selectively reacted with a dienophile in the presence of the less
reactive diene 5o, precluding the need for a separation of 4o and
5o. Thus, the Diels−Alder reaction of the nitrile-mediated α-
dienylated mixture of 4o and 5o (4o/5o = 80:20) with but-2-
ynedioic acid diethyl ester as a model dienophile in 1,4-dioxane at
100 °C for 5 h afforded the Diels−Alder adduct 8 in 92% yield
(based on diene 4o), and the less reactive diene 5o can be
recovered almost quantitatively (Scheme 5a). The oxidative
aromatization of 8 using 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ)18 afforded the α-arylated propionate 9a in 84%
yield. These two reactions could also be telescoped in a single pot
without isolation of the Diels−Alder adduct 8, producing 9 in
77% overall yield. With these results in hand, we next finally
attempted the tandem one-pot Blaise/vinylation/Diels−Alder/
oxidative aromatization reaction sequence starting from
Reformatsky reagent 1a to afford α-arylated propionate 9a in
40% overall yield (calculated on the basis of limiting reagent
nitrile) (Scheme 5b). Although the nitrile mediator remained in
the reaction mixture after the retro-Blaise reaction, it did not
interfere with the subsequent Diels−Alder reaction. However,
Scheme 2. Effects of α-Substituent (R1) on the Reaction
Pathway of Intermediate A with 1,3-Enynes
tandem reaction with α-substituted intermediate A (R1 ≠ H)
afforded a mixture of α-dienylated alkanoates 4 and 5, implying
that the retro-Blaise reaction occurred under these reaction
conditions (Scheme 2). Thus, the tandem reaction of α-methyl-
substituted intermediate A, formed by reaction of Reformatsky
reagent 1a with 3-phenylpropionitrile, with cyclohexenyne 2k at
100 °C for 24 h in 1,4-dioxane afforded an 80:20 mixture of α-
dienylated 4o and 5o in 73% yield (entry 1, Table 3). There was
no sign of the formation of the corresponding pyridine derivative
7, which was instead obtained in our previous work. The reaction
scope with respect to the Reformatsky reagent extends to the
synthesis of the methyl ester-(4p) and pentanoate-functionalized
diene 4q in good yields with 4/5 = 81:19 ratio (entries 2 and 3,
Table 3). Under the same reaction conditions, the seven- (2l)
and eight-membered carbocyclic enynes (2m) gave the
corresponding α-dienylated alkanoates 4r (entry 4, Table 3)
and 4s (entry 5, Table 3), respectively, in good yields. In contrast,
the cis-diphenyl-substituted acyclic 1,3-enyne 2n afforded the
fully conjugated trans-5t as a major product (entry 6, Table 3).
To gain a better understanding of the reaction mechanism, we
carried out deuterium-labeling experiments. As shown in Scheme
3a, no deuterium was incorporated into 4a and 5a upon
quenching the reaction with ND4Cl in D2O. This result clearly
indicates that the generated zinc dienolate D shown in Scheme 1
is protonated to produce 4a and 5a prior to workup. In addition,
the tandem reaction with deuterium-labeled 2a-d produced 50%
deuterium-labeled 4a-d and 5a-d, determined by comparison of
the signal intensities of the vinyl protons at 5.40 and 5.24 ppm
with methine proton at 3.70 ppm for 4a and the β-methyl
1
protons at 2.23 ppm for 5a in H NMR spectra (see the
Supporting Information) (Scheme 3b). The scrambling of the
proton and deuterium atoms at the methine and vinyl and of the
11486
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
a
Table 3. Nitrile-Mediated Intermolecular Addition of Reformatsky Reagents to 1,3-Enynes
a
The reaction conditions were as follows. The Reformatsky reagent 1, generated in situ from alkyl bromoalkanoate (2.6 mmol) and Zn (4.0 mmol),
was reacted with 3-phenylpropionitrile (2.0 mmol) in 1,4-dioxane (0.6 mL). A solution of 2 (4.2 mmol) in 1,4-dioxane (0.6 mL) was added after full
b
conversion of the nitrile to intermediate A (>95% by GC). The ratio of 4/5 was determined either by 1H NMR analysis of the crude product and/
c
or by the isolated yields of 4 and 5. Isolated yields (4 + 5) (the nitrile was used as a limiting reagent to maximize the formation of A, and the yield
was calculated on the basis of the limiting reagent).
Scheme 3. Deuterium-Labeling Experiments
excess amounts of DDQ (3.0 equiv) are necessary to complete
the oxidative aromatization reaction in this tandem sequence.
Under the same reaction conditions, the α-arylated alkanoates
9b−d could also be successfully synthesized in good yields.
The resulting vinylated intermediates are then directed through
bifurcating reaction pathways as a function of the presence of an
α-substituent. Although α-unsubstituted vinylated intermediates
afford vinylated enaminoesters or pyridines, α-substituted
vinylated intermediates undergo a retro-Blaise reaction to
generate zinc dienolate. Deuterium-labeling experiments suggest
that the zinc dienolates are protonated by acidic acetyletic
protons prior to workup to give the targeted α-vinylated and α-
dienylated alkanoates. When combined with a Diels−Alder
reaction and oxidative aromatization, our approach provides a
tandem one-pot method for the de novo synthesis of α-arylated
alkanoates. The retro-Blaise reaction is therefore established as a
CONCLUSIONS
■
We have developed a new nitrile-mediated tandem regioselective
addition of unstabilized zinc enolates (Reformatsky reagent) to
1-alkynes and 1,3-enynes. This reaction is made possible by a
reversible addition of enolates to a nitrile, generating a zinc aza-
enolate (Blaise reaction intermediate) that unlike zinc ester
enolates can add intermolecularly to 1-alkynes and 1,3-enynes.
11487
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
Scheme 4. Summary of Plausible Reaction Pathways for Tandem Reaction of the Blaise Reaction Intermediate A with 1-Alkynes
and 1,3-Enynes
Scheme 5. (a) Stepwise and (b) Tandem De Novo Construction of α-Arylated Alkanoates Based on the Nitrile-Mediated α-
Dienylation of Reformatsky Reagents with 1,3-Enynes
distilled from sodium benzophenone ketyl, and toluene was distilled
from CaH2. Anhydrous solvent was transferred with an oven-dried
syringe. All purchased reagents were used without further purification.
The 1,3-enynes 2l, 2m, and 2n were synthesized according to reported
procedures.19 The NMR spectra were recorded at 300 or 400 MHz for
1H and at 75 or 100 MHz for 13C. HRMS data were obtained by electron
ionization with a magnetic sector−electronic sector double-focusing
mass analyzer.
highly promising method to access the functionalized surrogates
of unstabilized enolates in carbon−carbon-bond-forming re-
actions.
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed in a nitrogen
atmosphere using standard Schlenk techniques. Reaction flasks were
flame-dried under a stream of nitrogen. THF and 1,4-dioxane were
11488
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
General Procedure for Tandem Addition of Reformatsky
Reagents to 1-Alkynes and 1,3-Enynes. To a stirred suspension of
commercial zinc dust (10 μm, 270 mg, 4.0 mmol) in THF (0.6 mL)
under reflux was added a solution of methanesulfonic acid in THF (1.0
M, 0.15 mL). After 5 min of stirring, 3-phenylpropionitrile (0.27 mL, 2.0
mmol) was added all at once. While maintaining reflux, alkyl
bromoalkanoate (2.6 mmol) was added over 1 h using a syringe
pump, and the reaction mixture was further stirred for 30 min. To this
reaction mixture was added a solution of 1-alkyne 2 (4.2 mmol) in THF
(0.6 mL). After 24 h of reflux, the reaction mixture was cooled to room
temperature, quenched with a saturated aqueous NH4Cl solution, and
extracted with ethyl acetate (20 mL x 3). The combined organic layers
were dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography to afford the corresponding 4 and 5. For the
compounds 4i/5i, 5n, 4o/5o, 4p/5p, 4q/5q, 4r/5r, 4s/5s, and 4t/5t,
the Blaise reactions were carried out at 80 °C in 1,4-dioxane instead of
THF, and the vinylation/retro-Blaise reaction was accomplished at 100
°C for 24 h. In the case of 4m/5m, the Blaise reaction/vinylation
reactions were carried out in THF, and then, for the retro-Blaise
reaction, the reaction mixture was diluted with DMF (3.0 mL) and
heated at 120 °C for 24 h. The ratios of 4 and 5 were determined either
by analysis of the crude 1H NMR analysis after short filtration through a
short plug of silica or by the isolated yield after silica gel column
chromatographic purification. The compound pairs 4l/5l, 4q/5q, and
4r/5r were not separable by silica gel chromatography. Consequently,
their NMR characterizations were performed by NMR spectra analysis
of the mixture of 4 and 5. The pure form of 5q and 5r could be isolated
after Diels−Alder reactions of the corresponding mixture of 4 and 5 with
but-2-ynedoic acid diethyl ester.
Ethyl 3-(4-Methoxyphenyl)-2-methylbut-3-enoate (4d) [CAS:
119139-90-1]. Yield: 78% (367 mg). Eluent: n-hexane/EtOAc = 20:1
to 10:1. Colorless liquid. 1H NMR (300 MHz, CDCl3) δ 1.16 (t, J = 7.1
Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H), 3.65 (q, J = 7.0 Hz, 1H), 3.79 (s, 3H),
4.10 (q, J = 7.1 Hz, 2H), 5.14 (s, 1H), 5.32 (s, 1H), 6.85 (d, J = 8.8 Hz,
2H), 7.33 (d, J = 8.8 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.1,
17.0, 44.6, 55.3, 60.7, 112.5, 113.7, 127.6, 133.4, 147.4, 159.2, 174.6 ppm.
Ethyl (2E)-3-(4-Methoxyphenyl)-2-methylbut-2-enoate (5d) [CAS:
1
61712-13-8]. Yield: 11% (50 mg). Colorless liquid. H NMR (300
MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 1.78 (d, J = 1.5 Hz, 3H), 2.24 (d,
J = 1.5 Hz, 3H), 3.82 (s, 3H), 4.26 (q, J = 7.1 Hz, 2H), 6.89 (d, J = 8.8 Hz,
2H), 7.09 (d, J = 8.8 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.4,
17.6, 23.3, 55.3, 60.4, 113.7, 124.8, 128.8, 135.7, 145.1, 158.7, 170.3 ppm.
Ethyl 3-(4-Fluorophenyl)-2-methylbut-3-enoate (4e). Yield: 75%
(332 mg). Eluent: n-hexane/EtOAc = 20:1. Colorless liquid. 1H NMR
(300 MHz, CDCl3) δ 1.16 (t, J = 7.1 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H),
3.63 (q, J = 7.1 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 5.22 (s, 1H), 5.34 (s,
1H), 6.98−7.03 (m, 2H), 7.33−7.37 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3) δ 14.2, 16.9, 44.8, 60.8, 114.2, 115.1, 115.4, 128.3 (d, J = 8.3 Hz),
137.2 (d, J = 3.0 Hz), 147.1, 162.5 (d, J = 246.9 Hz), 174.4 ppm. HRMS
calcd m/z for C13H15FO2 [M]+, 222.1056; found; 222.1054.
Ethyl (2E)-3-(4-Fluorophenyl)-2-methylbut-2-enoate (5e) [CAS:
1
61712-09-2]. Yield: 7% (16 mg). Pale-yellow liquid. H NMR (300
MHz, CDCl3) δ 1.35 (t, J = 7.1 Hz, 3H), 1.75 (d, J = 1.5 Hz, 3H), 2.23 (d,
J = 1.5 Hz, 3H), 4.26 (q, J = 7.1 Hz, 2H), 7.02−7.14 (m, 4H) ppm. 13C
NMR (75 MHz, CDCl3) δ 14.4, 17.5, 23.3, 60.6, 115.2, 115.5, 125.6,
129.1 (d, J = 8.3 Hz), 139.3 (d, J = 3.8 Hz), 144.2, 161.9 (d, J = 246.1
Hz), 170.0 ppm.
Ethyl 3-(2-Fluorophenyl)-2-methylbut-3-enoate (4f). Yield: 59%
(261 mg). Eluent: n-hexane/EtOAc = 20:1. Colorless liquid. 1H NMR
(300 MHz, CDCl3) δ 1.14 (t, J = 7.1 Hz, 3H), 1.37 (d, J = 7.1 Hz, 3H),
3.62 (q, J = 7.1 Hz, 1H) 4.07 (q, J = 7.1 Hz, 2H), 5.29 (s, 1H), 5.40 (s,
1H), 7.00−7.11 (m, 2H), 7.20−7.28 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3) δ 14.1, 16.5, 45.3 (d, J = 2.3 Hz), 60.7, 115.7 (d, J = 22.7 Hz),
117.3 (d, J = 1.5 Hz), 124.0 (d, J = 3.0 Hz), 129.2 (d, J = 8.3 Hz), 129.6
(d, J = 15.1 Hz), 130.6 (d, J = 3.8 Hz), 143.8, 159.8 (d, J = 246.9 Hz),
174.2 ppm. HRMS calcd m/z for C13H15FO2 [M]+, 222.1056; found;
222.1058.
Ethyl 2-Methyl-3-phenylbut-3-enoate (4a) [CAS: 25289-62-7].
Yield: 78% (320 mg). Eluent: n-hexane/EtOAc = 20:1. Colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.18 (t, J = 7.1 Hz, 3H), 1.42 (d, J = 7.1
Hz, 3H), 3.71 (q, J = 7.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 5.26 (s, 1H),
5.42 (s, 1H), 7.30−7.43 (m, 5H) ppm. 13C NMR (75 MHz, CDCl3) δ
14.1, 17.1, 44.6, 60.7, 114.0, 126.6, 127.7, 128.4, 141.2, 148.1, 174.5 ppm.
Ethyl (2E)-2-Methyl-3-phenylbut-2-enoate (5a) [CAS: 52094-27-6].
Yield: 10% (40 mg). Pale-yellow liquid. 1H NMR (300 MHz, CDCl3) δ
1.35 (t, J = 7.1 Hz, 3H), 1.75 (d, J = 1.5 Hz, 3H), 2.25 (d, J = 1.5 Hz, 3H),
4.27 (q, J = 7.1 Hz, 2H), 7.13−7.16 (m, 2H), 7.27−7.30 (m, 1H), 7.33−
7.39 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.5, 17.5, 23.3, 60.5,
125.0, 127.1, 127.4, 128.4, 143.6, 145.5, 170.2 ppm.
Ethyl 2-Methyl-3-(3-methylphenyl)but-3-enoate (4b). Yield: 77%
(334 mg). Eluent: n-hexane/EtOAc = 20:1. Colorless liquid. 1H NMR
(300 MHz, CDCl3) δ 1.17 (t, J = 7.1 Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H),
2.35 (s, 3H), 3.66 (q, J = 7.1 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 5.20 (s,
1H), 5.36 (s, 1H), 7.07−7.10 (m, 1H), 7.17−7.24 (m, 3H) ppm. 13C
NMR (75 MHz, CDCl3) δ 14.2, 17.2, 21.6, 44.6, 60.7, 113.7, 123.7,
127.3, 128.3, 128.4, 137.9, 141.2, 148.3, 174.6 ppm. HRMS calcd m/z for
C14H18O2 [M]+, 218.1307; found; 218.1305.
Ethyl (2E)-2-Methyl-3-(3-methylphenyl)but-2-enoate (5b). Yield:
8% (37 mg). Pale-yellow liquid. 1H NMR (300 MHz, CDCl3) δ 1.34 (t, J
= 7.1 Hz, 3H), 1.75 (d, J = 1.4 Hz, 3H), 2.24 (d, J = 1.4 Hz, 3H), 2.36 (s,
3H), 4.26 (q, J = 7.1 Hz, 2H), 6.93−6.96 (m, 2H), 7.07−7.10 (m, 1H),
7.22−7.27 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.5, 17.6, 21.6,
23.3, 60.5, 124.4, 124.8, 127.9, 128.0, 128.3, 138.1, 143.6, 145.7, 170.2
ppm. HRMS calcd m/z for C14H18O2 [M]+, 218.1307; found; 218.1306.
Ethyl 2-Methyl-3-(4-methylphenyl)but-3-enoate (4c) [CAS:
253663-98-8]. Yield: 81% (354 mg). Eluent: n-hexane/EtOAc = 20:1
to 10:1. Colorless liquid. 1H NMR (300 MHz, CDCl3) δ 1.16 (t, J = 7.1
Hz, 3H), 1.38 (d, J = 7.1 Hz, 3H), 2.33 (s, 3H), 3.66 (q, J = 7.1 Hz, 1H),
4.10 (q, J = 7.1 Hz, 2H), 5.18 (s, 1H), 5.36 (s, 1H), 7.12 (d, J = 7.9 Hz,
2H), 7.28 (d, J = 8.2 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.2,
17.1, 21.2, 44.6, 60.7, 113.2, 126.4, 129.1, 137.4, 138.2, 147.9, 174.6 ppm.
Ethyl (2E)-2-Methyl-3-(4-methylphenyl)but-2-enoate (5c) [CAS:
61712-12-7]. Yield: 8% (35 mg). Colorless liquid. 1H NMR (300 MHz,
CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 1.77 (d, J = 1.5 Hz, 3H), 2.24 (d, J =
1.5 Hz, 3H), 2.36 (s, 3H), 4.26 (q, J = 7.1 Hz, 2H), 7.04 (d, J = 8.1 Hz,
2H), 7.17 (d, J = 7.9 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.6,
17.6, 21.3, 23.3, 60.5, 124.8, 127.4, 129.1, 136.8, 140.6, 145.5, 170.3 ppm.
Ethyl (2E)-3-(2-Fluorophenyl)-2-methylbut-2-enoate (5f). Yield:
11% (50 mg). Eluent: n-hexane/EtOAc = 20:1. Yellow liquid. 1H NMR
(300 MHz, CDCl3) δ 1.35 (t, J = 7.1 Hz, 3H), 1.72 (d, J = 1.2 Hz, 3H),
2.25 (d, J = 1.2 Hz, 3H), 4.27 (q, J = 7.1 Hz, 2H), 7.05−7.17 (m, 3H),
7.23−7.30 (m, 1H) ppm. 13C NMR (75 MHz, DMSO) δ 14.1, 17.1, 22.0
60.3, 115.8 (d, J = 21.9 Hz), 124.7 (d, J = 3.8 Hz), 126.7, 129.5 (d, J = 3.8
Hz), 129.7 (d, J = 7.6 Hz), 138.5, 157.9 (d, J = 243.9 Hz), 168.3 ppm.
HRMS calcd m/z for C13H15FO2 [M]+, 222.1056; found; 222.1057.
Ethyl 3-(4-Bromophenyl)-2-methylbut-3-enoate (4g). Yield: 77%
1
(439 mg). Eluent: n-hexane/EtOAc = 20:1. Yellow liquid. H NMR
(300 MHz, CDCl3) δ 1.17 (t, J = 7.1 Hz, 3H), 1.39 (d, J = 7.1 Hz, 3H),
3.63 (q, J = 7.1 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 5.26 (s, 1H), 5.39 (s,
1H), 7.26 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H) ppm. 13C NMR
(75 MHz, CDCl3) δ 14.1, 16.9, 44.5, 60.8, 114.6, 121.7, 128.2, 131.4,
140.0, 147.0, 174.2 ppm. HRMS calcd m/z for C13H15BrO2 [M]+,
282.0255; found; 282.0255.
Ethyl (2E)-3-(4-Bromophenyl)-2-methylbut-2-enoate (5g) [CAS:
61712-11-6]. Yield: 12% (33 mg). Yellow liquid. 1H NMR (300 MHz,
CDCl3) δ 1.36 (t, J = 7.1 Hz, 3H), 1.76 (d, J = 1.4 Hz, 3H), 2.23 (d, J =
1.4 Hz, 3H), 4.28 (q, J = 7.1 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.50 (d, J
= 8.4 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.4, 17.5, 23.1, 60.6,
121.1, 12.7, 129.2, 131.7, 142.3, 143.9, 169.9 ppm.
Ethyl 3-(4-Cyanophenyl)-2-methylbut-3-enoate (4h). Yield: 57%
(261 mg). Eluent: n-hexane/EtOAc = 10:1. Colorless liquid. 1H NMR
(300 MHz, CDCl3) δ 1.16 (t, J = 7.1 Hz, 3H), 1.41 (d, J = 7.1 Hz, 3H),
3.67 (q, J = 7.1 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 5.39 (s, 1H), 5.49 (s,
1H), 7.50 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.6 Hz, 2H) ppm. 13C NMR
(75 MHz, CDCl3) δ 14.0, 16.8, 44.1, 60.9, 111.2, 116.7, 118.8, 127.2,
132.1, 145.7, 146.6, 173.7 ppm. HRMS calcd m/z for C14H15NO2 [M]+,
229.1103; found; 229.1099.
Ethyl (2E)-2-Methyl-3-(4-cyanophenyl)but-2-enoate (5h) [CAS:
1
160425-18-3]. Yield: 3% (14 mg). Colorless liquid. H NMR (300
11489
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 1.35 (t, J = 7.1 Hz, 3H), 1.73 (d, J = 1.4 Hz, 3H), 2.23 (d,
J = 1.4 Hz, 3H), 4.27 (q, J = 7.1 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.67
(d, J = 8.2 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.4, 17.5, 22.8,
60.8, 111.1, 118.9, 126.6, 128.4, 132.5, 143.0, 148.3, 169.5 ppm.
Ethyl 2-Methyl-3-methylidene-5-phenylpentanoate (4i). Yield:
(d, J = 1.2 Hz, 2H), 7.34−7.37 (m, 3H), 7.45−7.48 (m, 2H) ppm. 13
C
NMR (75 MHz, CDCl3) δ 14.4, 18.0, 59.9, 117.2, 126.4, 128.6, 129.0,
142.3, 155.6, 166.9 ppm.
(3E)-3-(1-Phenylethylidene)dihydrofuran-2(3H)-one (E-5n) [CAS:
67404-97-1]. Yield: 38% (143 mg). Eluents: n-hexane/EtOAc = 5:1 to
1
1
2:1. Yellow solid. H NMR (300 MHz, CDCl3) δ 2.57 (t, J = 2.2 Hz,
45% (209 mg). Eluent: n-hexane/EtOAc = 10:1. Colorless liquid. H
3H), 2.84−2.89 (m, 2H), 4.22 (t, J = 7.2 Hz, 2H), 7.24−7.28 (m, 2H),
7.33−7.43 (m, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 19.6, 29.6, 64.7,
120.7, 126.7, 128.3, 128.5, 142.5, 151.1, 171.0 ppm.
(3Z)-3-(1-phenylethylidene)dihydrofuran-2(3H)-one (Z-5n) [CAS:
157494-86-5]. Yield: 35% (128 mg). Brown solid. 1H NMR (300 MHz,
CDCl3) δ 2.14 (t, J = 1.7 Hz, 3H), 2.96−3.01 (m, 2H), 4.30 (t, J = 7.4
Hz, 2H), 7.19−7.22 (m, 2H), 7.29−7.37 (m, 3H) ppm. 13C NMR (75
MHz, CDCl3) δ 25.1, 28.3, 64.0, 120.1, 127.4, 127.8, 127.9, 139.9, 150.4,
168.7 ppm.
NMR (300 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.32 (d, J = 7.1 Hz,
3H), 2.30−2.48 (m, 2H), 2.76−2.83 (m, 2H), 3.19 (q, J = 7.1 Hz, 1H),
4.16 (q, J = 7.1 Hz, 2H), 4.97 (s, 1H), 5.01 (s, 1H), 7.21−7.23 (m, 3H),
7.28−7.35 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.3, 16.4, 34.4,
36.5, 46.0, 60.7, 111.4, 126.0, 128.5, 142.0, 147.8, 174.6 ppm. HRMS
calcd m/z for C15H20O2 [M]+, 232.1463; found; 232.1461.
Ethyl (2E)-2,3-Dimethyl-5-phenylpent-2-enoate (5i). Yield: 10%
(46 mg). Yellowish liquid. 1H NMR (300 MHz, CDCl3) δ 1.30 (t, J = 7.1
Hz, 3H), 1.81 (s, 3H), 2.02 (s, 3H), 2.39−2.45 (m, 2H), 2.69−2.74 (m,
2H), 4.19 (q, J = 7.1 Hz, 2H), 7.18−7.24 (m, 3H), 7.26−7.31 (m, 2H)
ppm. 13C NMR (75 MHz, CDCl3) δ 14.4, 15.3, 21.1, 33.7, 38.3, 60.2,
123.6, 126.2, 128.5, 128.6, 141.7, 145.2, 170.1 ppm. HRMS calcd m/z for
C14H16O4 [M]+, 232.1463; found; 232.1462.
Methyl 4-(4-Methoxy-3-methyl-4-oxobut-1-en-2-yl)benzoate (4j).
Yield: 62% (273 mg). Eluent: n-hexane/EtOAc = 10:1 to 7:1. Pale-
yellow liquid. 1H NMR (300 MHz, CDCl3) δ 1.40 (d, J = 7.1 Hz, 3H),
3.65 (s, 3H), 3.67−3.74 (m, 1H), 3.92 (s, 3H), 5.33 (s, 1H), 5.48 (s,
1H), 7.45 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H) ppm. 13C NMR
(75 MHz, CDCl3) δ 17.1, 44.3, 52.2 (52.18), 52.2 (52.21), 115.9, 126.5,
129.4, 129.8, 145.6, 147.2, 166.9, 174.7 ppm. HRMS calcd m/z for
C14H16O4 [M]+, 248.1049; found; 248.1046.
Methyl 4-[(2E)-4-Methoxy-3-methyl-4-oxobut-2-en-2-yl]benzoate
(5j). Yield: 4% (10 mg). Eluent: n-hexane/EtOAc = 10:1 to 7:1. Yellow
liquid. 1H NMR (300 MHz, CDCl3) δ 1.74 (d, J = 1.3 Hz, 3H), 2.26 (d, J
= 1.3 Hz, 3H), 3.81 (s, 3H), 3.93 (s, 3H), 7.22 (d, J = 8.2 Hz, 2H), 8.04
(d, J = 8.2 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 17.5, 23.0, 51.8,
52.3, 125.5, 127.5, 129.1, 129.9, 145.1, 148.3, 167.0, 170.1 ppm. HRMS
calcd m/z for C14H16O4 [M]+, 248.1049; found; 248.1045.
Ethyl 3-(Cyclohex-1-en-1-yl)-2-methylbut-3-enoate (4o). Yield:
58% (243 mg). Eluent: n-hexane/EtOAc = 20:1. Pale-yellow liquid.
1H NMR (300 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H), 1.33 (d, J = 7.1
Hz, 3H), 1.55−1.61 (m, 2H), 1.63−1.70 (m, 2H), 2.12−2.18 (m, 4H),
3.51 (q, J = 7.1 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.95 (s, 1H), 5.13 (s,
1H), 5.88−5.92 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.3, 17.4,
22.2, 23.0, 25.9, 26.6, 42.3, 60.6, 109.8, 124.7, 135.7, 148.2, 175.3 ppm.
HRMS calcd m/z for C13H20O2 [M]+, 208.1463; found; 208.1461.
Ethyl (2E)-3-(Cyclohex-1-en-1-yl)-2-methylbut-2-enoate (5o).
1
Yield: 15% (61 mg). Yellow liquid. H NMR (300 MHz, CDCl3) δ
1.31 (t, J = 7.1 Hz, 3H), 1.58−1.69 (m, 4H), 1.83 (d, J = 1.4 Hz, 3H),
1.95−2.00 (m, 2H), 2.01 (d, J = 1.4 Hz, 3H), 2.05−2.09 (m, 2H), 4.20
(q, J = 7.1 Hz, 2H), 5.34−5.40 (m, 1H) ppm. 13C NMR (75 MHz,
CDCl3) δ 14.5, 16.9, 20.8, 22.2, 22.9, 25.0, 26.9, 60.2, 122.5, 123.2, 140.2,
149.1, 170.3 ppm. HRMS calcd m/z for C13H20O2 [M]+, 208.1463;
found; 208.1464.
Methyl 3-(Cyclohex-1-en-1-yl)-2-methylbut-3-enoate (4p). Yield:
67% (261 mg). Eluents: n-hexane/EtOAc = 20:1 to 10:1. Pale-yellow
liquid. 1H NMR (300 MHz, CDCl3) δ 1.31 (d, J = 7.1 Hz, 3H), 1.52−
1.59 (m, 2H), 1.61−1.69 (m, 2H), 2.08−2.19 (m, 4H), 3.51 (q, J = 7.1
Hz, 1H), 3.64 (s, 3H), 4.93 (s, 1H), 5.11 (s, 1H), 5.86−5.88 (m, 1H)
ppm. 13C NMR (75 MHz, CDCl3) δ 17.4, 22.1, 22.9, 25.9, 26.4, 42.0,
51.9, 109.8, 124.6, 135.4, 148.0, 175.7 ppm. HRMS calcd m/z for
C12H18O2 [M]+, 194.1307; found; 194.1307.
Methyl 2-Methyl-3-phenylbut-3-enoate (4k) [CAS: 75072-22-9].
Yield: 72% (274 mg). Eluent: n-hexane/EtOAc = 20:1. Colorless liquid.
1H NMR (300 MHz, CDCl3) δ 1.38 (d, J = 7.1 Hz, 3H), 3.64 (s, 3H),
3.68−3.71 (m, 1H), 5.22 (s, 1H), 5.39 (s, 1H), 7.24−7.39 (m, 5H) ppm.
13C NMR (75 MHz, CDCl3) δ 17.1, 44.4, 52.0, 114.1, 126.4, 127.7,
128.4, 140.9, 147.9, 175.0 ppm.
Methyl (2E)-3-(Cyclohex-1-en-1-yl)-2-methylbut-2-enoate (5p).
Yield: 16% (62 mg). Yellow liquid. H NMR (300 MHz, CDCl3) δ
1
Methyl (2E)-2-Methyl-3-phenylbut-2-enoate (5k) [CAS: 14367-28-
3]. Yield: 8% (30 mg). Colorless liquid. 1H NMR (300 MHz, CDCl3) δ
1.75 (d, J = 1.5 Hz, 3H), 2.26 (d, J = 1.5 Hz, 3H), 3.80 (s, 3H), 7.12−7.15
(m, 2H), 7.26−7.29 (m, 1H), 7.33−7.39 (m, 2H) ppm. 13C NMR (75
MHz, CDCl3) δ 17.5, 23.4, 51.6, 124.7, 127.2, 127.3, 128.5, 143.6, 146.3,
170.4 ppm.
1.58−1.72 (m, 4H), 1.84 (d, J = 1.4 Hz, 3H), 1.96−2.10 (m, 4H), 2.03
(d, J = 1.4 Hz, 3H), 3.74 (s, 3H), 5.36−5.39 (m, 1H) ppm. 13C NMR (75
MHz, CDCl3) δ 16.9, 20.9, 22.2, 22.8, 25.0, 26.9, 51.4, 122.2, 123.2,
140.2, 149.9, 170.5 ppm. HRMS calcd m/z for C12H18O2 [M]+,
194.1307; found; 194.1309.
Mixture of Ethyl 2-(1-Phenylethenyl)pentanoate and Ethyl (2E)-2-
(1-Phenylethylidene)pentanoate (4l/5l = 86:14). Yield: 78% (362
mg). Eluent: n-hexane/EtOAc = 20:1. Colorless liquid. 1H NMR (300
MHz, CDCl3) δ 0.77 (t, J = 7.3 Hz, 0.14 × 3H), 0.89 (t, J = 7.3 Hz, 0.86 ×
3H), 1.19 (t, J = 7.1 Hz, 0.86 × 3H), 1.27−1.40 (m, 0.86 × 2H + 0.14 ×
5H), 1.59−1.71 (m, 0.86 × 1H), 1.84−1.94 (m, 0.86 × 1H), 2.08−2.14
(m, 0.14 × 2H), 2.16 (s, 0.14 × 3H), 3.52 (dd, J = 8.4, 6.4 Hz, 0.86 ×
1H), 4.13 (q, J = 7.1 Hz, 0.86 × 2H), 4.27 (q, J = 7.1 Hz, 0.14 × 2H), 5.27
(s, 0.86 × 1H), 5.38 (s, 0.86 × 1H), 7.12−7.14 (m, 0.14 × 2H), 7.24−
7.41 (m, 0.86 × 5H + 0.14 × 3H) ppm. 13C NMR (75 MHz, CDCl3) δ
14.0 (13.96), 14.0 (14.02), 14.2, 14.4, 21.1, 21.2, 22.4, 23.4, 33.1, 34.4,
50.4, 60.4, 60.7, 113.8, 114.5, 126.5, 126.6, 127.0, 127.3, 127.6, 128.4,
129.1, 130.9, 141.6, 143.2 (143.16), 143.2 (143.24), 147.2, 170.3, 174.1
ppm. HRMS calcd m/z for C15H20O2 [M + Na]+, 255.1361; found;
255.1360.
Ethyl 3-Phenylbut-3-enoate (4m) [CAS: 5633-64-7]. Yield: 3% (5
mg). Eluent: n-hexane/EtOAc = 20:1. Colorless liquid. 1H NMR (300
MHz, CDCl3) δ 1.18 (t, J = 7.1 Hz, 3H), 3.51 (s, 2H), 4.11 (q, J = 7.1 Hz,
2H), 5.23 (s, 1H), 5.54 (s, 1H), 7.25−7.36 (m, 3H), 7.42−7.45 (m, 2H)
ppm. 13C NMR (75 MHz, CDCl3) δ 14.2, 41.5, 60.9, 116.3, 125.9, 127.9,
128.5, 140.0, 141.1, 171.5 ppm.
Mixture of Ethyl 2-[1-(Cyclohex-1-en-1-yl)ethenyl]pentanoate
(4q) and Ethyl (2E)-2-[1-(Cyclohex-1-en-1-yl)ethylidene]pentanoate
(5q) (4q/5q = 81:19). Yield: 70% (331 mg). Eluent: n-hexane/EtOAc =
1
20:1. Colorless liquid. For the major compound 4q: H NMR (300
MHz, CDCl3) δ 0.91 (t, J = 7.3 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.27−
1.38 (m, 2H), 1.52−1.70 (m, 6H), 2.10−2.20 (m, 4H), 3.37 (dd, J = 8.9,
5.7 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.99 (s, 1H), 5.12 (s, 1H), 6.92−
6.94 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.1, 14.3, 21.3, 22.2,
22.9, 23.0, 25.9, 26.6, 34.6, 47.8, 60.5, 110.1, 124.6, 135.9, 147.2, 174.7
ppm. HRMS calcd m/z for C15H24O2 [M]+, 236.1776; found; 236.1775.
Ethyl (2E)-2-[1-(Cyclohex-1-en-1-yl)ethylidene]pentanoate (5q).
Isolated after the Diels−Alder reaction of a mixture of 4q and 5q with
but-2-ynedioic acid diethyl ester. Colorless liquid. 1H NMR (300 MHz,
CDCl3) δ 0.86 (t, J = 7.3 Hz, 3H), 1.25−1.38 (m, 5H), 1.54−1.70 (m,
4H), 1.93 (s, 3H), 1.96−2.02 (m, 2H), 2.04−2.11 (m, 2H), 2.21−2.26
(m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 5.37−5.39 (m, 1H) ppm. 13C NMR
(75 MHz, CDCl3) δ 14.3, 14.5, 20.7, 22.2, 22.9, 25.0, 27.5, 33.0, 60.2,
122.9, 128.5, 139.7, 146.8, 170.5 ppm.
Mixture of Ethyl 3-(Cyclohept-1-en-1-yl)-2-methylbut-3-enoate
(4r) and Ethyl (2E)-3-(Cyclohept-1-en-1-yl)-2-methylbut-2-enoate
(5r) (4r/5r = 69:31). Yield: 76% (338 mg). Eluent: n-hexane/EtOAc =
1
Ethyl (2E)-3-Phenylbut-2-enoate (5m) [CAS: 1504-72-9]. Yield:
54% (206 mg). Pale-yellow liquid. 1H NMR (300 MHz, CDCl3) δ 1.31
(t, J = 7.1 Hz, 3H), 2.58 (d, J = 1.2 Hz, 3H), 4.21 (q, J = 7.1 Hz, 2H), 6.13
20:1. Pale-yellow liquid. For the major compound 4r: H NMR (300
MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H), 1.31 (d, J = 7.1 Hz, 3H), 3.41 (q,
J = 7.1 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.91 (s, 1H), 5.07 (s, 1H), 5.93
11490
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
(t, J = 6.8 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.3, 17.1, 26.5,
26.7, 28.5, 30.9, 32.6, 43.0, 60.5, 110.1, 129.2, 144.7, 150.4, 175.1 ppm.
HRMS calcd m/z for C14H22O2 [M]+, 222.1620; found; 222. 1618.
Ethyl (2E)-3-(Cyclohept-1-en-1-yl)-2-methylbut-2-enoate (5r). Iso-
lated after the Diels−Alder reaction of a mixture of 4r and 5r with but-2-
ynedioic acid diethyl ester. Colorless liquid. 1H NMR (300 MHz,
CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H), 1.51−1.62 (m, 4H), 1.74−1.82 (m,
2H), 1.87 (d, J = 1.4 Hz, 3H), 2.01 (d, J = 1.4 Hz, 3H), 2.15−2.22 (m,
4H), 4.21 (q, J = 7.1 Hz, 2H), 5.56 (t, J = 6.4 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3) δ 14.5, 17.3, 20.7, 27.2, 27.3, 28.7, 32.3, 32.6, 60.2,
121.5, 128.9, 146.0, 150.6, 170.4 ppm.
concentrated under reduced pressure. The residue was purified by silica
chromatography to afford 9a in 84% (233 mg) yield. To conduct these
two reaction steps in one pot without isolation of 8, the 1,4-dioxane
solvent was evaporated after the Diels−Alder reaction, and toluene and
DDQ were added to the residue. The resulting mixture was stirred for 2
h at toluene refluxing to afford 9a in 77% (232 mg) yield.
General Procedure for Tandem De Novo Construction of α-
Arylated Alkanotates from Reformatsky Reagents. To a stirred
suspension of commercial zinc dust (10 μm, 270 mg, 4.0 mmol) in 1,4-
dioxane (0.5 mL) was added a solution of methanesulfonic acid in 1,4-
dioxane (1.0 M, 0.15 mL) at 80 °C bath temperature. After 5 min of
stirring, 3-phenylpropionitrile (0.27 mL, 2.0 mmol) was added all at
once. While maintaining the same temperature, alkyl bromoalkanoate
(3.0 mmol) was added over 1 h using a syringe pump, and the reaction
mixture was further stirred for 30 min. The reaction mixture was heated
at 100 °C, and then cyclic 1,3-enyne 2 (4.2 mmol) was added. After 24 h
of stirring at the same temperature, a solution of but-2-ynedioic acid
diethyl ester (0.4 mL, 2.4 mmol) in 1,4-dioxane (3.0 mL) was added, and
the reaction mixture was stirred at the same temperature for an
additional 5 h. The reaction mixture was cooled to room temperature,
filtered through Celite, and washed with ethyl acetate (15 mL × 3), and
then the filtrate was concentrated under reduced pressure. The resulting
mixture was diluted with toluene (6.0 mL) and added to a stirred
solution of 2,3-dichloro-5,6,-dicyano-1,4-benzoquinone (DDQ, 1.36 g,
6.0 mmol) in toluene (4.0 mL) at room temperature. The reaction
mixture was stirred for 2 h under refluxing toluene. After cooling to
room temperature, the reaction mixture was filtered through a plug of
silica gel with the aid of three 30 mL portions of ethyl acetate, and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica chromatography to afford the corresponding α-arylated
alkanoates 9a−d.
Ethyl 3-(Cyclooct-1-en-1-yl)-2-methylbut-3-enoate (4s). Yield:
1
74% (349 mg). Eluent: n-hexane/EtOAc = 20:1. Colorless liquid. H
NMR (300 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H), 1.34 (d, J = 7.1 Hz,
3H), 1.41−1.56 (m, 8H), 2.18−2.25 (m, 2H), 2.42−2.46 (m, 2H), 3.51
(q, J = 7.1 Hz, 1H), 4.13 (qd, J = 7.1, 2.0 Hz, 2H), 5.01 (s, 1H), 5.20 (s,
1H), 5.84 (t, J = 8.2 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.2,
17.3, 26.0, 26.2, 27.1, 27.5, 28.9, 30.3, 42.4, 60.5, 110.9, 127.6, 139.3,
147.5, 175.2 ppm. HRMS calcd m/z for C15H24O2 [M]+, 236.1776;
found; 236.1774.
Ethyl (2E)-3-(Cyclooct-1-en-1-yl)-2-methylbut-2-enoate (5s).
Yield: 14% (67 mg). Pale-yellow liquid. 1H NMR (300 MHz, CDCl3)
δ 1.32 (t, J = 7.1 Hz, 3H), 1.52−1.57 (m, 8H), 1.88 (d, J = 1.3 Hz, 3H),
2.06 (d, J = 1.3 Hz, 3H), 2.17−2.20 (m, 2H), 2.22−2.32 (m, 2H), 4.22
(q, J = 7.1 Hz, 2H), 5.40 (t, J = 8.2 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3) δ 14.5, 17.3, 21.8, 26.4, 26.5, 29.1, 29.5 (29.47), 29.5 (29.53),
60.2, 122.5, 126.9, 142.7, 149.5, 170.5 ppm. HRMS calcd m/z for
C15H24O2 [M]+, 236.1776; found; 236.1774.
Ethyl (4Z)-2-Methyl-3-methylidene-4,5-diphenylpent-4-enoate
(4t). Yield: 28% (172 mg). Eluents: n-hexane/EtOAc = 40:1 to 20:1.
Yellow liquid. 1H NMR (300 MHz, CDCl3) δ 1.16 (t, J = 7.1 Hz, 3H),
1.32 (d, J = 7.1 Hz, 3H), 3.24 (q, J = 7.1 Hz, 1H), 3.90−4.07 (m, 2H),
5.34 (s, 1H), 5.49 (s, 1H), 6.75 (s, 1H), 7.19−7.25 (m, 1H), 7.29−7.40
(m, 5H), 7.46−7.51 (m, 2H), 7.51−7.58 (m, 2H) ppm. 13C NMR (75
MHz, CDCl3) δ 14.2, 16.2, 44.4, 60.7, 118.8, 127.3, 127.5, 127.8, 128.3,
128.4, 129.1, 129.2, 137.3, 142.1, 143.1, 145.5, 174.2 ppm. HRMS calcd
m/z for C21H22O2 [M]+, 306.1620; found; 306.1617.
Ethyl (2E,4E)-2,3-Dimethyl-4,5-diphenylpenta-2,4-dienoate (5t).
Yield: 46% (281 mg). Yellow liquid. 1H NMR (300 MHz, CDCl3) δ 1.39
(t, J = 7.1 Hz, 3H), 1.76 (d, J = 1.3 Hz, 3H), 2.22 (d, J = 1.3 Hz, 3H), 4.31
(q, J = 7.1 Hz, 2H), 6.87 (s, 1H), 7.25−7.30 (m, 1H), 7.32−7.44 (m,
5H), 7.47−7.53 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3) δ 14.4, 16.9,
21.0, 60.4, 126.2, 126.7, 126.8, 127.5, 127.9, 128.6 (128.56), 128.6
(128.60), 128.8, 137.0, 139.6, 142.3, 144.2, 169.3 ppm. HRMS calcd m/
z for C21H22O2 [M]+, 306.1620; found; 306.1617.
Diethyl 4-(1-Ethoxy-1-oxopropan-2-yl)-3,5,6,7,8,8a-hexahydro-
naphthalene-1,2-dicarboxylate (8). (Mixture of diastereomers, d.r. ≃
1
6:4 by H NMR). Eluent: n-hexane/EtOAc = 5:1. Colorless viscous
liquid. 1H NMR (400 MHz, CDCl3) δ 1.07−1.29 (m, 14H), 1.35−1.48
(m, 1H), 1.54−1.68 (m, 1H), 1.68−1.80 (m, 2H), 1.84−1.94 (m, 1H),
2.60−2.78 (m, 1H + 0.6 × 1H), 2.81−2.88 (m, 1H), 2.89- 3.06 (m, 1H +
0.4 × 1H), 3.58 (q, J = 7.1 Hz, 0.6 × 1H), 3.60 (q, J = 7.1 Hz, 0.4 × 1H),
3.98−4.07 (m, 2H), 4.07−4.23 (m, 4H) ppm. 13C NMR (100 MHz,
CDCl3) δ 14.0, 14.1, 14.8, 15.3, 26.5, 26.6, 27.3, 27.6, 27.8, 27.9, 29.8,
33.9, 34.0, 40.4, 40.5, 42.2, 42.3, 60.5, 60.9, 121.8, 121.9, 128.9 (128.88),
128.9 (129.92), 133.0, 137.8, 137.9, 167.1, 168.5 (168.46), 168.5
(168.50), 174.1 (174.06), 174.1 (174.11) ppm.
Diethyl 4-(1-Ethoxy-1-oxopropan-2-yl)-5,6,7,8-tetrahydronaph-
thalene-1,2-dicarboxylate (9a). Yield: 301 mg (40%, calculated on
the basis of the limiting reagent nitrile). Eluent: n-hexane/diethyl ether
= 6:1. Colorless viscous liquid. 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J
= 7.1 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.44 (d, J
= 7.1 Hz, 3H), 1.71−1.83 (m, 4H), 2.67−2.76 (m, 3H), 2.82−2.89 (m,
1H), 3.94 (q, J = 7.1 Hz, 1H), 4.10 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H),
4.38 (q, J = 7.2 Hz, 2H), 7.72 (s, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ 14.2, 14.3, 17.8, 22.0, 22.5, 26.9, 27.0, 40.7, 61.0, 61.3, 61.4,
125.3, 125.7, 134.6, 134.9, 140.6, 140.7, 165.8, 169.7, 174.2 ppm. HRMS
calcd m/z for C21H28O6 [M]+, 376.1886; found; 376.1885.
Ethyl 2-Methyl-3-oxo-5-phenyl-2-(1-phenylethenyl)pentanoate
(6). Yield: 26% (201 mg). Eluent: n-hexane/EtOAc = 10:1. Colorless
liquid. 1H NMR (300 MHz, CDCl3) 1.18 (t, J = 7.1 Hz, 3H), 1.50 (s,
3H), 2.80−2.98 (m, 4H), 4.14 (q, J = 7.1 Hz, 2H), 5.19 (s, 1H), 5.39 (s,
1H), 7.12−7.18 (m, 5H), 7.23−7.27 (m, 5H) ppm. 13C NMR (75 MHz,
CDCl3) δ 14.0, 21.3, 30.5, 41.5, 61.7, 65.7, 118.9, 126.2, 127.7, 127.9,
128.2, 128.5 (128.50), 128.5 (128.53), 140.4, 141.1, 148.0, 172.0, 206.6
ppm. HRMS calcd m/z for C22H24O3 [M + Na]+, 359.1623; found;
359.1625.
Procedures for Stepwise and Tandem Synthesis of 9a from the
Isolated Mixture of 4o and 5o with an 80:20 Ratio. To a stirred
solution of a mixture of 4o and 5o (208 mg, 1 mmol, 4o/5o = 80:20) in
1,4-dioxane (2.0 mL) was added but-2-ynedioic acid diethyl ester (0.18
mL, 1.1 mmol) at room temperature. The reaction mixture was stirred at
100 °C for 5 h. After cooling to room temperature, the reaction mixture
was concentrated under reduced pressure. The residue was purified by
silica-gel column chromatography to afford the stereoisomeric mixture 8
(d.r. ≃ 6:4) as a colorless liquid (279 mg, 92% yield, based on 4o). The
less reactive diene 5o (41 mg) was recovered quantitatively. For the
oxidative aromatization of 8, a solution of 8 (265 mg, 0.70 mmol) in
toluene (1.0 mL) was added to a stirred solution of 2,3-dichloro-5,6,-
dicyano-1,4-benzoquinone (DDQ, 207 mg, 0.91 mmol) in toluene (1.0
mL). The reaction mixture was stirred for 2 h at reflux. After cooling to
room temperature, the reaction mixture was filtered through a short plug
of silica gel with the aid of three 10 mL portions of ethyl acetate and
Diethyl 4-(1-Ethoxy-1-oxopropan-2-yl)-6,7,8,9-tetrahydro-5H-
benzo[7]annulene-1,2-dicarboxylate (9b). Yield: 264 mg (34%,
calculated on the basis of the limiting reagent nitrile). Eluent: n-
1
hexane/diethyl ether = 6:1. Pale-yellow viscous liquid. H NMR (300
MHz, CDCl3) δ 1.17 (t, J = 7.1 Hz, 3H), 1.29−1.36 (m, 6H), 1.44 (d, J =
7.1 Hz, 3H), 1.52−1.68 (m, 4H), 1.70−1.80 (m, 2H), 2.73−2.76 (m,
2H), 2.85−2.90 (m, 2H), 3.97 (q, J = 7.1 Hz, 1H), 4.09 (qd, J = 7.1, 1.1
Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 7.72 (s, 1H)
ppm. 13C NMR (75 MHz, CDCl3) δ 14.1, 14.2, 18.1, 26.6, 26.8, 29.3,
31.2, 31.7, 42.5, 60.9, 61.2, 61.3, 125.2, 127.2, 133.8, 139.1, 141.0, 147.3,
165.6, 169.9, 174.2 ppm. HRMS calcd m/z for C22H30O6 [M]+,
390.2042; found; 390.2041.
Diethyl 4-(1-Ethoxy-1-oxopropan-2-yl)-5,6,7,8,9,10-
hexahydrobenzo[8]annulene-1,2-carboxylate (9c). Yield: 367 mg
(45%, calculated on the basis of the limiting reagent nitrile). Eluent: n-
1
hexane/diethyl ether = 4:1. Colorless viscous liquid. H NMR (300
11491
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ 1.18 (t, J = 7.1 Hz, 3H), 1.34−1.45 (m, 10H), 1.48 (d, J
= 7.1 Hz, 3H), 1.60−1.88 (m, 4H), 2.80−2.85 (m, 2H), 2.86−2.92 (m,
1H), 2.96−3.05 (m, 1H), 4.02−4.17 (m, 3H), 4.33 (q, J = 7.1 Hz, 2H),
4.42 (q, J = 7.1 Hz, 2H), 7.83 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3)
δ 14.2 (14.15), 14.2 (14.20), 14.3, 19.0, 25.8, 26.6, 27.3, 30.0, 30.5, 31.4,
41.0, 61.0, 61.4, 61.5, 126.0, 126.7, 134.4, 139.1, 140.3, 144.5, 165.8,
170.1, 174.3 ppm. HRMS calcd m/z for C23H32O6 [M]+, 404.2199;
found; 404.2196.
Diethyl 4-(1-Ethoxy-1-oxopentan-2-yl)-5,6,7,8-tetrahydronaph-
tahalene-1,2-carboxylate (9d). Yield: 347 mg (41%, calculated on
the basis of the limiting reagent nitrile and the ratio of reactive diene 4q
shown in Table 3). Eluents: n-hexane/diethyl ether = 6:1 to 4:1.
Colorless viscous liquid. 1H NMR (300 MHz, CDCl3) δ 0.89 (t, J = 7.3
Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H), 1.20−1.38 (m, 8H), 1.60−1.81 (m,
5H), 2.02−2.15 (m, 1H), 2.67−2.77 (m, 3H), 2.87−2.95 (m, 1H), 3.85
(t, J = 7.5 Hz, 1H), 4.02−4.15 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 4.39 (q,
J = 7.1 Hz, 2H), 7.80 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 13.9,
14.1 (14.09), 14.1 (14.13), 14.2, 20.9, 22.0, 22.5, 26.9, 27.1, 35.1, 45.8,
60.8, 61.2, 61.4, 125.2, 125.8, 134.5, 134.8, 139.3, 140.9, 165.8, 169.7,
173.6 ppm. HRMS calcd m/z for C23H32O6 [M]+, 404.2199; found;
404.2198.
16, 3147. (g) Nakamura, M.; Fujimoto, T.; Endo, K.; Nakamura, E. Org.
Lett. 2004, 6, 4837.
(4) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 13002. (b) Nakamura, M. Pure Appl. Chem. 2006, 78, 425.
(c) Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am.
Chem. Soc. 2007, 129, 5264. (d) Nakamura, M.; Endo, K.; Nakamura, E.
Org. Lett. 2005, 7, 3279. (e) Nakamura, M.; Endo, K.; Nakamura, E. Adv.
Synth. Catal. 2005, 347, 1681. (f) Zhang, J.; Blazecka, P. G.; Angell, P.;
Lovdahl, M.; Curren, T. T. Tetrahedron 2005, 61, 7807. (g) Angell, P.;
Blazecka, P. G.; Lovdahl, M.; Zhang, J. J. Org. Chem. 2007, 72, 6606.
(h) Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J.
Am. Chem. Soc. 2008, 130, 4492.
(5) Mn-enolate of 1,3-dicarbonyl compounds reacted with 2 equiv of 1-
alkynes to afford benzene derivatives. (a) Tsuji, H.; Yamagata, K.-i.;
Fujimoto, T.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 7792.
(b) Kuninobu, Y.; Sishi, M.; Yudha, S., S.; Takai, K. Org. Lett. 2008, 10,
3009. (c) Yoshika, A.; Zhang, S.-L.; Yamagata, K.-i.; Tsuji, H.;
Nakamura, E. J. Am. Chem. Soc. 2009, 131, 4099.
(6) (a) Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett. 2005, 7, 4823.
(b) For Re-catalyzed insertion of terminal alkyne to cyclic β-ketoesters,
see: Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006, 128,
11368. (c) Kuninobu, Y.; Morita, J.; Nishi, M.; Kawata, A.; Takai, K. Org.
Lett. 2009, 11, 2535.
(7) For Ir-catalyzed addition of 1,3-dicarbonyls to internal alkynes, see:
Onodera, G.; Kato, M.; Kawano, R.; Kometani, Y.; Takeuchi, R. Org.
Lett. 2009, 11, 5038.
(8) (a) Yamaguchi, M.; Tsukagoshi, T.; Arisawa, M. J. Am. Chem. Soc.
1999, 121, 4074. (b) Arisawa, M.; Akamatsu, K.; Yamaguchi, M. Org.
Lett. 2001, 3, 789. (c) Arisawa, M.; Amemiya, R.; Yamaguchi, M. Org.
Lett. 2002, 4, 2209. (d) Amemiya, R.; Nishimura, Y.; Yamaguchi, M.
Synthesis 2004, 1307. (e) Yamaguchi, M.; Nishimura, Y. Chem. Commun.
2008, 35.
(9) (a) Nakahira, H.; Tyu, I.; Ikebe, M.; Oku, Y.; Ogawa, A.; Kambe,
N.; Sonoda, N.; Murai, S. J. Org. Chem. 1992, 57, 17. (b) Yamaguchi, M.;
Hayashi, A.; Hirama, M. J. Am. Chem. Soc. 1993, 115, 3362.
(c) Yamaguchi, M.; Sehata, M.; Hayashi, A.; Hirama, M. J. Chem. Soc.,
Chem. Commun. 1993, 1708.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of 4a-d50%, 5a-d50%, 4a−t, 5a−t, 6, 8,
and 9a−d. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sanggi@ewha.ac.kr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(10) Nishimoto, Y.; Moritoh, M.; Yasuda, M.; Baba, A. Angew. Chem.,
Int. Ed. 2009, 48, 4577.
We acknowledge financial support of this work from the Korea
Research Foundation (NRF-2011-0016344 and NRF-2009-
0083525). Y. S. Chun thanks Ewha Womans University for RP
support. We thank Prof. J. Bouffard at Ewha Womans University
for helpful discussions and Dr. Sung Hong Kim at the Daegu
Center of Korea Basic Science Institute for mass spectral analysis.
(11) (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478.
(b) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 987.
(12) (a) Rathke, M. W.; Weipert, P. In Zinc Enolates: The Reformatsky
and Blaise Reaction in Comprehensive Organic Reactions; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 2, pp 277−299. (b) Rao, H. S. P.; Rafi, S.;
Padmavathy, K. Tetrahedron 2008, 64, 8037. (c) Hannick, S. M.; Kishi,
Y. J. Org. Chem. 1983, 48, 3833.
(13) (a) Chun, Y. S.; Lee, K. K.; Ko, Y. O.; Shin, H.; Lee, S.-g. Chem.
Commun. 2008, 5098. (b) Chun, Y. S.; Ryu, K. Y.; Ko, Y. O.; Hong, J. Y.;
Hong, J.; Shin, H.; Lee, S.-g. J. Org. Chem. 2009, 74, 7556. (c) Chun, Y.
S.; Ko, Y. O.; Shin, H.; Lee, S.-g. Org. Lett. 2009, 11, 3414. (d) Ko, Y. O.;
Chun, Y. S.; Park, C.-L.; Kim, Y.; Shin, H.; Ahn, S.; Hong, J.; Lee, S.-g.
Org. Biomol. Chem. 2009, 7, 1132. (e) Ko, Y. O.; Chun, Y. S.; Kim, Y.;
Kim, S. J.; Shin, H.; Lee, S.-g. Tetrahedron Lett. 2010, 51, 6893. (f) Kim, J.
H.; Lee, S.-g. Org. Lett. 2011, 13, 1350. (g) Chun, Y. S.; Lee, J. H.; Kim, J.
H.; Ko, Y. O.; Lee, S.-g. Org. Lett. 2011, 13, 6390. (h) Chun, Y. S.; Ryu,
K. Y.; Kim, J. H.; Shin, H.; Lee, S.-g. Org. Biomol. Chem. 2011, 9, 1317.
(i) Kim, J. H.; Shin, H.; Lee, S.-g. J. Org. Chem. 2012, 77, 1560. (j) Kim, J.
H.; Lee, S.-g. Synthesis 2012, 44, 1464. (k) Kim, J. H.; Chun, Y. S.; Shin,
H.; Lee, S.-g. Synthesis 2012, 44, 1809. (l) Chun, Y. S.; Kim, J. H.; Choi,
S. Y.; Ko, Y. O.; Lee, S.-g. Org. Lett. 2012, 14, 6358. (m) Chun, Y. S.;
Xuan, Z.; Kim, J. H.; Lee, S.-g. Org. Lett. 2013, 15, 3162.
DEDICATION
■
This paper is dedicated to Professor Teruaki Mukaiyama in
celebration of the 40th anniversary of the Mukaiyama aldol
reaction.
REFERENCES
■
(1) (a) Marek, I.; Chinkov, N.; Bannon-Tenne, D. In Metal-Catalyzed
Cross Coupling Reactions, 2nd ed.; Diederich, F., de Meijere, A., Eds.;
Wiley-VCH: Weinheim, Germany, 2004; Chapter 7, p 395. (b) Lothiois,
E.; Meyer, C. In The Chemistry of Organozinc Compounds; Rappoport, Z.,
Marek, I., Eds.; Wiley: Chichester, U.K., 2006; Chapter 19, p 863.
(c) Per
2008, 32, 594. (d) Den
2010, 110, 2366.
́
ez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. New J. Chem.
́
es, F.; Perez-Luna, A.; Chemla, F. Chem. Rev.
́
̀
(2) (a) Zhang, X.-M.; Bordwell, F. G.; Van Der Puy, M.; Fried, H. E. J.
Org. Chem. 1993, 58, 3060. (b) Bordwell, F. G.; Drucker, G. E.;
Andersen, N. H.; Denniston, A. J. Am. Chem. Soc. 1986, 108, 7310.
(3) (a) Seefelder, M. Justus Lieb. Ann. Chem. 1962, 652, 107. (b) Shulte,
(14) Chang and co-workers reported that a nitrile can be used as an
accelerator in Rh-catalyzed conversion of aldoximes to amides, see: Kim,
M.; Lee, J.; Lee, H.-Y.; Chang, S. Adv. Synth. Catal. 2009, 351, 1807.
(15) The direct reaction of a Reformatsky reagent 1a with
phenylacetylene 2a did not proceed at all, and phenylacetylene was
recovered after hydrolytic workup.
K. E.; Rucker, G.; Feldkamp, J. Chem. Ber. 1972, 105, 24. (c) Gaudemar,
̈
M. Bull. Soc. Chim. Fr. 1966, 3113. (d) Bertrand, M. T.; Courtois, G.;
Miginiac, L. Tetrahedron Lett. 1974, 15, 1945. (e) Bertrand, M. T.;
Courtois, G.; Miginiac, L. C. R. Acad. Sci., Paris., Ser. C 1975, 999.
(f) Bertrand, M. T.; Courtois, G.; Miginiac, L. Tetrahedron Lett. 1975,
(16) trans-5a can be synthesized by direct reaction of a Reformatsky
reagent 1a with acetophenone in the presence of stoichiometric amount
11492
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493

The Journal of Organic Chemistry
Article
of diphenylphosphite in a 45% yield. See: Cui, H.; Li, Y.; Zhang, S. Org.
Biomol Chem. 2012, 10, 2862.
(17) The Pd-catalyzed α-arylations of Reformatsky reagents with
halogenated aromatics could also afford α-arylated alkanoates. For
selected papers, see: (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res.
2003, 36, 234. (b) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 4976. (c) Hama, T.; Ge, S.; Hartwig, J. F. J. Org. Chem.
2013, 78, 8250.
(18) For the oxidative aromatization of 1,3-dienes with DDQ, see:
(a) Auvinet, A.-L.; Harrity, J. P. A.; Hilt, G. J. Org. Chem. 2010, 75, 3893.
(b) Hilt, G.; Galbiati, F. Org. Lett. 2006, 8, 2195. (c) Hilt, G.; Luers, S.;
Smolko, K. I. Org. Lett. 2005, 7, 251. (d) Hilt, G.; Smolk, K. I. Angew.
Chem., Int. Ed. 2003, 42, 2795.
(19) (a) Yoshida, M.; Hayashi, M.; Shishido, K. Org. Lett. 2009, 11,
3414. (b) Odedra, A.; Datta, S.; Liu, R.-S. J. Org. Chem. 2007, 72, 3289.
11493
dx.doi.org/10.1021/jo402015n | J. Org. Chem. 2013, 78, 11483−11493