Rerouting radical cascades: Intercepting the homoallyl ring expansion in enyne cyclizations via C-S scission

Article abstract of DOI:10.1021/jo5012043

The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3-exo-trig/fragmentation) ring expansion to afford the benzylic radical necessary for the final aromatizing C-C bond fragmentation. The interception of the intermediate 5-exo-trig product via β-scission of a properly positioned weak C-S bond provides direct mechanistic evidence for the 5-exo cyclization/ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild synthesis of Bu₃Sn-functionalized naphthalenes.

Full text of DOI:10.1021/jo5012043

Article
pubs.acs.org/joc
Rerouting Radical Cascades: Intercepting the Homoallyl Ring
Expansion in Enyne Cyclizations via C−S Scission
Sayantan Mondal, Brian Gold, Rana K. Mohamed, Hoa Phan, and Igor V. Alabugin*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States
S
* Supporting Information
ABSTRACT: The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the
combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of
four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3-exo-trig/fragmentation) ring expansion to afford
the benzylic radical necessary for the final aromatizing C−C bond fragmentation. The interception of the intermediate 5-exo-trig
product via β-scission of a properly positioned weak C−S bond provides direct mechanistic evidence for the 5-exo cyclization/
ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild
synthesis of Bu3Sn-functionalized naphthalenes.
effects are used in the reaction design.11−13 Considering the
INTRODUCTION
■
unexpected regioselectivity of the overall transformation, we set
out to investigate how the nature of the substituent at the alkene
controls the competition between 5-exo-trig and 6-endo-trig
pathways without affecting the high chemo- and regioselectivity
of the initial radical attack at the enyne. We had previously shown
that the reaction selectivity stems from kinetic sorting14 of
the equilibrating “pool” of radicals via the lowest activation
barrier escape route. However, the role of alkene substitution in
changing the nature of the final cyclization step has so far
remained unclear. In particular, we were interested in under-
standing whether it involves selective stabilization of the 6-endo
transition state (TS) or relative destabilization of the 5-exo TS or
whether the situation is even more complex.
In particular, the observed change in selectivity could rather
originate from ring expansion of the initially formed 5-exo
intermediate into the six-membered product and not from direct
6-endo trig cyclization, as shown in Scheme 2. Such expansion,
rendered possible by the presence of an adjacent π-bond and
the intrinsically low barriers of radical 3-exo cyclizations,10d has
been implicated in a variety of radical rearrangements such as
Dowd−Beckwith,15 neophyl,27 O-neophyl,16,17 and homoallyl18,19
rearrangements (Scheme 2).
The alkyne functional group is a high-energy moiety whose
versatile reactivity1 can be harnessed for useful transformations.2
In particular, radical cascade cyclizations3 of alkynes4 provide a
convenient route to structures desirable in conjugated functional
materials5 such as polycyclic aromatics.6
We recently reported that the Bu3Sn-mediated radical
cyclization of aromatic enynes provides a facile route to
Sn-substituted indenes7 and naphthalenes.8 The selectivity of
this transformation is controlled by substitution at the alkene end
(Scheme 1). Reactants with radical stabilizing groups (CO2R/Ph)
afford indenes, while −CH2X (X = H, alkyl, OR, NR2, Ph)
substitution gives six-membered products. In the cases of
X = OR, NR2, Ph, the cyclizations afford aromatic products by
the concomitant loss of the −CH2X group via β-scission of a C−C
bond.9 The energetic penalty for breaking a strong σ-bond is
compensated by the aromaticity gained in the product and by the
rational design of radical leaving groups stabilized by two-center,
three-electron bonding between the radical and the lone pair of
an adjacent heteroatom (or benzylic stabilization). In the latter
“self-terminating” radical cyclization, alkenes serve as synthetic
equivalents of alkynes, providing fully aromatized products
without external oxidants.
On the basis of the stereoelectronic preferences in alkyne and
alkene cyclizations,10 we were intrigued by the formation of
formal 6-endo products. Radical attack at π-bonds intrinsically
favors the exo path,10 unless special factors such as steric or polar
Received: May 29, 2014
Published: July 10, 2014
© 2014 American Chemical Society
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Scheme 1. Kinetic Self-Sorting and Alkene Substituent Effects on Reactivity of Enynes: (Bottom) Radical-Stabilizing Groups
Favoring Hydrogen Atom Abstraction To Form Indenes; (Top) Radical Leaving Groups Fragmenting To Form Naphthalenes
Scheme 2. Top: Indirect (Rearrangement) Routes for the Formation of “6-endo” Products (Top) and Family of Radical
a
Rearrangements Proceeding via a Three-Membered-Ring Intermediate (Bottom)
a
The rate constants are from refs 20 and 21.
If such rearrangement is involved prior to the terminating
fragmentation step, the overall reaction cascade’s selectivity is
guided through a sequence of two radical cyclizations and
two radical fragmentations by utilizing a single radical from an
equilibrating radical mixture. The combination of experimental
and computational results, provided herein, elucidate the
mechanism of this transformation.
either be 5-exo-trig or 6-endo-trig; however, fragmentation can
only occur from the six-membered radical. If 5-exo cyclization
is preferred, this radical must undergo further rearrangement/
ring expansion18 to give the formal 6-endo radical. This can be
initiated by 3-exo attack at the vicinal benzene ring as a neophyl
expansion (blue pathway, Figure 2) or the “isolated” double
bond as a homoallyl expansion (red pathway, Figure 2).
In lieu of labor-intensive isotope labeling, we utilized enynes
1b,c to differentiate between the two possible ring expansion
pathways: neophyl vs homoallyl. By this simple strategy, the alkyl
substituents at the two alkene carbons were used to track the
position of the reacting carbon atoms (Figure 3). The lack of
carbon transposition in each respective cyclization product for
enynes 1b,c eliminated the neophyl expansion path (blue) in
Figure 2, which would require transient loss of aromaticity. While
this observation does not rule out the 6-endo cyclization, it
suggests that the ring expansion proceeds via the homoallyl
rearrangement, initiated by cyclization onto the “isolated” double
bond (red pathway).
RESULTS AND DISCUSSION
■
To understand the switch in reactivity, a variety of enynes were
synthesized with different alkene substituents. Depending on the
availability of the starting materials, we used strategies based on
sequential Wittig reaction and Sonogashira coupling, as shown in
Scheme 3 (see the Experimental Section for details).
In the presence of Bu3Sn radical in refluxing toluene, enynes
1a−c cyclized to the substituted naphthalenes selectively in good
yields (Figure 1). To avoid complications associated with the
partial hydrolysis of tin-containing compounds on silica, the
Bu3Sn moiety was removed by protodestannylation prior to
purification. In the case of 1b,c, the starting enyne was ob-
tained as a mixture of cis and trans isomers (see the Supporting
Information for details); however, upon cyclization, each
substrate still gave a high yield of a single naphthalene product.
Naphthalene formation has to involve initial attack at the triple
bond (Figure 2). As discussed above, the mode of cyclization can
In agreement with the experimental data, the computed
activation barriers suggest that neophyl rearrangement should be
significantly slower than the homoallyl path (Figure 4, 18.8 vs
13.6 kcal/mol, respectively). The barrier for the 3-exo closure
onto the “isolated” alkene is much lower than the barrier for
cyclization which disrupts aromaticity; however, the former is
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Scheme 3. Synthetic Approaches to the Synthesized Library of Enynes
From the calculated energy profile for enyne 1a, it is apparent
that 5-exo-trig cyclization is more facile than 6-endo cyclization
(ΔG⧧(398 K) = 7.3 vs 9.9 kcal/mol; Figure 5). At the relatively
high reaction temperatures where addition processes are
disfavored by the negative entropy, the free energy for β-scission
of the initially formed radical back to the starting enyne is lower
than the barrier for 5-exo-trig cyclization (6.3 vs 7.3 kcal/mol),
suggesting a precascade equilibration between enyne reactant
and acyclic vinyl radical intermediate.
The 5-exo-trig cyclization is ∼20 kcal/mol exergonic and can
be considered irreversible from a practical point of view. From
this point, two 3-exo-trig cyclizations are possible to initiate
either the homoallyl or neophyl rearrangement. As discussed
above, the homoallyl rearrangement has a lower activation barrier
and provides a product which, albeit considerably strained, is still
only slightly uphill from the 5-exo product (∼2 kcal/mol). The
relatively low thermodynamic penalty for the 3-exo step likely
stems from the combination of benzylic stabilization and α-Sn
effect at the radical center.22
Trapping the 5-exo Radical. An interesting consequence
from the above computational study is that the relatively high
(13.6 kcal/mol) barrier for the 3-exo-trig step presented an
opportunity for trapping the 5-exo radical and intercepting the
ring expansion pathways. A literature search for the possible ways
for outcompeting the 3-exo-trig cyclization presented several
choices.
For example, the elegant work of Crich and co-workers re-
ported that relatively stable radicals can be trapped prior to
intramolecular reactions by accelerating intermolecular H
abstraction via polarity reversal catalysis.20,23 Successful utiliza-
tion of this strategy using catalytic amounts of PhSeH allowed
trapping of the 5-exo radical prior to the ring expansion re-
arrangement. This intermolecular trapping was possible because
the initially formed vinyl (or aryl) radical was highly reactive and
underwent rapid 5-exo-trig cyclization,24 generating a relatively
Figure 1. Tin-mediated enyne cyclization/fragmentation to naphthalene.
still quite significant due to accumulation of strain in the tricyclic
moiety.
Both the neophyl and homoallyl ring openings are exergonic
(∼16 and ∼12 kcal/mol relative to the 5-exo radical) because the
less strained six-membered radicals enjoy significant stabilization by
additional electronic effects: allylic vs benzylic resonances and the
through-bond (TB) interaction between the radical center and the
lone pair of the exocyclic oxygen atom.8 The six-membered radical
resulting from the neophyl rearrangement is more stable due to the
greater stabilization provided by the allylic resonance relative to the
benzylic resonance in addition to α-Sn stabilization.22
We had found earlier that such TB stabilizing interactions
increase even further in the TS for the subsequent C−C bond
fragmentation.8 Due to this selective TS stabilization effect and
assistance by the developing aromatic character of the final
product, the barrier for the fragmentation of the relatively strong
(C−C) bond is relatively small (∼20 vs ∼24 kcal/mol relative to
the respective 6-endo radical for the red and blue pathways,
respectively).
Our further computational studies focused on the competition
between homoallyl and direct 6-endo pathways given in Figure 2.
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Figure 2. Plausible mechanisms for the formation of the observed naphthalene products. Direct 6-endo cyclization and the 5-exo/3-exo cascade with the
participation of an alkene do not lead to carbon transposition in the product. In contrast, the 5-exo/3-exo cascade with the involvement of an aromatic
system would lead to alkene carbon transposition.
stable alkyl radical (Figure 6). Trapping of this longer-lived alkyl
radical gave the 5-exo product as the major product.23 This
method was successful for both the neophyl and homoallyl
rearrangements.
In our case, the situation is less favorable because our reaction
pathway is initiated from the least stable equilibrating radical,
which is formed reversibly and is present in a relatively small
amount. As a consequence, the increase in intermolecular
H-abstraction rate did not allow us to obtain the 5-exo product.
Instead, addition of a catalytic amount of thiol gave an
inseparable mixture of reduced alkyne products,8 presumably
Figure 3. Cyclizations of substituted alkenes do not display carbon
transposition, ruling out the neophyl pathway in Figure 2.
because the radical pool is depleted when the more stable radicals
Figure 4. Calculated free energy profile for the two possible ring expansions (neophyl (blue) and homoallyl (red)) at the UM062X/LanL2DZ level of
theory. ΔG values (in kcal/mol) are calculated at 384 K.
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Figure 5. Calculated free energy profile for the Sn-mediated cyclization/fragmentation at the UM062X/LanL2DZ level of theory. ΔG values (in kcal/mol)
are calculated at 384 K.
Figure 6. Intermolecular trapping of 5-exo radical prior to ring expansion using H atom abstraction (HAA) and polarity reversal catalysis.
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Figure 7. Intramolecular diversions of reactivity away from the ring expansion pathway involve H-abstraction, alternative faster cyclizations, or β-scission
of a weak bond.
(incapable of cyclization) find a suitable intermolecular reaction
path.
in three reactions in addition to the ring expansion: further
cyclization, H-abstraction, or fragmentation via β-scission of a
weak C−S bond. The only observed products stemmed from the
β-scission, followed by subsequent cyclization. Although the
authors did not allude to the potential use of the fragmentation as
a mechanistic probe for the rearrangement, they did note that
this process was able to efficiently outcompete other reactions.23
Considering the above and the relative ease of incorporating
an allylic sulfide in the reactant, we decided to test whether
β-scission of a weak C−S vicinal bond28,29 can be utilized for the
interception of the 5-exo radical prior to ring expansion (Figure 8).
Indeed, the reaction of allylic sulfide gave mostly five-
membered products. The absence of the alkylthio moiety in
the products indicated that the 5-exo radical is successfully
intercepted via β-C−S scission (Figure 9). A very small amount
(∼4%) of the naphthalene product 3a may originate directly via
the 6-endo path, presumably due to the smaller ΔG⧧ difference
between the 5-exo and 6-endo pathways for this substrate
(0.6 kcal/mol, Figure 10) relative to X = OMe (2.6 kcal/mol).
The smaller 5-exo/6-endo difference for the alkylthio-substituted
enyne allows direct 6-endo-trig cyclization to compete with the
initial 5-exo-trig cyclization.
Since trapping via H-abstraction was not a viable option for
the 5-exo radical in our systems, we turned to intramolecular
alternatives (Figure 7). Curran had introduced a tethered alkyne
to show that facile 6-exo-dig cyclization or intramolecular
H-abstraction can compete against the 3-exo-trig cyclization
(Figure 7).25
Alternatively, Wulff and co-workers26 used “radical clock”
strategies based on cyclopropane ring opening24 to investigate
whether cascading radical cyclizations of bis-vinyl ethers involved
a sequence of 5-exo-trig addition followed by ring expansion
instead of direct 6-endo-trig cyclization. Interestingly, one of the
key observations pointing to the more complex mechanism was
the fragmentation of a C−O bond observed upon altering one of
the vinyl substituents (Figure 7, right).
We were attracted to the possibility of using β-scission of a
C−S bond as a way to intercept the ring expansion pathway. An
early report of Parker and co-workers disclosed that C−S scission
successfully intercepted the neophyl rearrangement.27 However,
our system is more challenging because the homoallyl rearrange-
ment is a faster process that is harder to intercept.
An indication that such an approach can be successful was
given by a more recent work of Journet et al., who provided
evidence suggesting that C−S bond scission can intercept the
more rapid homoallyl rearrangement in the radical cascades of
acyclic vinyl sulfides (Figure 7, bottom).28 In this case, the radical
generated after the first cyclization could potentially participate
Computational analysis confirms that the successful diversion
of the homoallyl ring expansion results from outcompeting the
usually facile 3-exo-trig cyclization (Figure 10). Rapid β-scission
of the C−S bond has a calculated barrier of only 4.3 kcal/mol, in
comparison to 13.8 kcal/mol for the 3-exo path. The fragmented
thiyl radical is relatively reactive and may assist in isomerization
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Figure 8. Planned trapping of 5-exo radical via β-scission of a weakened C−X bond.
Figure 9. Alternate reactivity observed for thio-substituted enynes.
Figure 10. Calculated free energy profile (UM062X/LanL2DZ) for thio-substituted enynes. Energies are given in kcal/mol. ΔG values are calculated
at 384 K.
of the initially formed nonconjugated dienes into two conjugated
diene products, the major of which is derived from the benzylic
radical stabilized by the adjacent C−Sn bonds.22
The structure of the major indene isomer was confirmed via
single-crystal X-ray analysis of the Diels−Alder product with
N-phenylmaleimide (Figure 11).
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Figure 11. Diels−Alder trapping of diene product (left) and single-crystal X-ray structure (right).
While removal of tin was generally conducted prior to
characterization, the direction of tin attack can be confirmed via
Stille coupling or iodination. Such reactivity illustrates a synthetic
advantage of the “tin handle” for facile functionalization of the
naphthalene core. Not only is the Bu3Sn radical a synthetic
equivalent of the H radical for the preparation of pristine hydro-
carbons via radical cyclizations but it also offers other synthetic
opportunities via reactions with suitable electrophilic reagents.
Through either direct cross-coupling or iodination followed by
coupling, one can generate highly substituted naphthalene
derivatives that are difficult to prepare from the parent aromatic
core (Figure 12).
Figure 13. Proposed mechanistic diversion from the homoallyl ring
expansion path.
TB interactions, which become even stronger in the frag-
mentation TS.8 The self-terminating fragmentation8 affords
substituted naphthalene products and stabilized radicals which
do not seem to provide efficient propagation.
Diversion away from the ring expansion pathway is possible in
the respective allyl sulfides, where the weak C−S bond readily
undergoes β-scission after the initial 5-exo-trig cyclization.
Isomerization provides indene and fulvene products. While
other mechanistic probes for diverting reactivity away from ring
expansion exist, this method benefits from simple incorporation
of the fragmenting group into starting materials.
Figure 12. Initial substitution along with tin as a functional handle
provides naphthalene building blocks.
Oxidative closure of aromatic substituents can afford larger
polycyclic aromatic hydrocarbon structures. Investigation of such
reactivity is underway and will be reported in due course, as well
as expansion of this reaction toward larger systems.
EXPERIMENTAL SECTION
■
General Procedures. Toluene and THF were obtained from a
Glass Contour Solvent Purification System. Hexanes for column
chromatography and preparatory thin-layer chromatography was
distilled prior to use. All other solvents were used as purchased.
Column chromatography was performed using silica gel (60 Å), and
preparatory thin-layer chromatography was performed using a 1000 μm
glass-backed plate containing UV dye. Unless otherwise noted, 1H NMR
CONCLUSIONS
■
We have found a new and efficient radical method for the
synthesis of substituted naphthalene building blocks by using
radical-stabilizing substitution at the allylic position in the enyne
system. The experimental and computational evidence converges
on the mechanism proposed in Figure 13. All substrates undergo
kinetic self-sorting via 5-exo-trig cyclization of the least stable of
the rapidly equilibrating radicals as the major pathway. This
transformation illustrates the versatility of radical reactivity, as
small electronic perturbations lead to large changes in observed
reactivity. While alkene substitution does not alter the cyclization
mode, decreased stabilization of the cyclized radicals can allow
for further reactivity: i.e., ring expansion/fragmentation.
spectra were run on 400 and 600 MHz spectrometers in CDCl3 and 13
C
NMR spectra were run on 100 and 150 MHz spectrometers in CDCl3.
Proton chemical shifts are given relative to the residual proton signal
of CDCl3 (7.26 ppm). Carbon chemical shifts were internally referenced
to the CDCl3 (77.23 ppm) signal. All J coupling values are reported in
hertz (Hz).
Preparation of Wittig Salt: Ethyl (Triphenylphosphoranylidene)-
acetate. Ethyl bromoacetate (2.9 mL, 26.7 mmol) was added dropwise
into a solution of triphenylphosphine (7 g, 26.7 mmol) in benzene at
room temperature. It was stirred for 4−5 h. The separated solid was
filtered using a Buchner funnel and the residue washed with hexane. The
resulting white solid was taken up in benzene (200 mL) and a solution of
15 g of NaOH in 100 mL of water was added to it. The mixture was
When X = OMe, the 5-exo radical undergoes homoallyl18 ring
expansion (3-exo-trig followed by cyclopropyl opening),
affording the formal 6-endo radical. This radical is stabilized via
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stirred until both layers became clear. The benzene layer was dried over
sodium sulfate and concentrated. The salt was recrystallized from
distilled petroleum ether (60−80 °C) to provide 8.9 g (96% yield) of
white solid.
Synthesis of Compound A1 by Wittig Reaction. Ethyl
(triphenylphosphoranylidene)acetate (2.80 g, 8.17 mmol) was added
to a solution of bromobenzaldehyde (1.0 g, 5.4 mmol) in dry DCM
(dichloromethane) at 0 °C and stirred for 6 h at room temperature. The
solvent was then evaporated under vacuum. The colorless oil was
partitioned between ethyl acetate (100 mL) and water (50 mL). The
organic layer was washed with water and brine and dried over Na2SO4. It
was then filtered and evaporated to give an oil from which the title
compound C1 was isolated by column chromatography (Si-gel, PE/EA
15/1). Yield: 1.3 g (95%); State: colorless oil.
DIBAL-H Reduction of α,β-Unsaturated Ester A1 (A2). A THF
solution of compound A1 (2.0 g, 7.8 mmol) was cooled to 0 °C.
Diisobutylaluminum hydride (DIBAL-H; 1.0 M in hexane, 15 mL,
15 mmol) was slowly added to this solution under nitrogen. The re-
action mixture was stirred for 6 h, quenched with aqueous NH4Cl
solution (20 mL), and extracted with ethyl acetate (100 mL). The
extract was washed with brine solution, dried over MgSO4, and con-
centrated under reduced pressure. The residue was eluted with 10% ethyl
acetate in hexane through a silica column to afford A2 as a colorless oil
(92%).
added dropwise to the mixture. The aqueous phase was extracted with
diethyl ether (4 × 50 mL), and the combined organic phase was washed
with brine (3 × 50 mL), dried over sodium sulfate, and concentrated in
vacuo. Flash chromatography (5% ethyl acetate in hexanes) yielded ester
B1 as a clear oil in 93% yield.
DIBAL-H Reduction of α,β-Unsaturated Ester B1 to B2. B2 was
synthesized using the same procedure described for the synthesis of
compound A2.
(E)-1-Bromo-2-(4-methoxybut-2-en-2-yl)benzene (B3). B3
was synthesized using the procedure described for the synthesis of
compound A3. Chromatographic purification (5% ethyl acetate in
hexane) afforded compound B3 (95% yield) as a colorless oil: Rf =
0.6 (10% ethyl acetate in hexane); 1H NMR (400 MHz; CDCl3) δ 7.53
(1H, d, J = 8.0 Hz), 7.26−7.22 (1H, m), 7.19−7.17 (1H, m), 7.12−7.09
(1H, m), 5.55 (1H, tm), 4.12 (2H, d, J = 6.6 Hz), 3.40 (3H, d, J = 0.7
Hz), 2.02 (3H, s); 13C NMR (100 MHz; CDCl3) δ 145.6, 140.1, 132.7,
129.9, 128.4, 127.3, 127.2, 121.9, 68.8, 56.0, 18.0; HRMS (EI, TOF)
calcd for C11H13BrO [M]+ 240.0150, found 240.0141; IR (neat, cm−1)
3052, 2198, 1479.
(E)-1-(4-Methoxybut-2-en-2-yl)-2-(phenylethynyl)benzene
(1b). This compound was obtained using the procedure described for
the synthesis of 1a. Chromatographic purification (5% ethyl acetate in
hexane) afforded compound 1b (92% yield) as a brown oil: Rf =
0.6 (10% ethyl acetate in hexane); 1H NMR (400 MHz; CDCl3) δ 7.56
(1H, d, J = 7.6 Hz), 7.53−7.49 (2H, m), 7.37−7.33 (3H, m), 7.29−7.25
(3H, m), 5.80 (1H, m), 4.19 (2H, d, J = 6.6 Hz), 3.42 (3H, s), 2.19
(3H, s).13C NMR (100 MHz; CDCl3) δ 147.3, 139.6, 132.8, 131.6 (2C),
128.5 (2C), 128.4, 128.3, 128.2, 127.1, 126.9, 123.7, 121.1, 92.8, 89.2,
69.3, 58.0, 18.0; HRMS (EI, TOF) calcd for C19H18O [M]+ 262.1358,
found 262.1351; IR (neat, cm−1) 3065, 2240, 1498, 966.
(E)-1-Bromo-2-(3-methoxyprop-1-en-1-yl)benzene (A3). To
a suspension of NaH (60% dispersion in mineral oil) in THF (20 mL)
was added 2-bromocinnamyl alcohol A2 (1.0 g, 4.7 mmol) at room
temperature. The mixture was stirred for 100 min at room temperature,
after which MeI (0.9 mL, 14 mmol, 3 equiv) was added in one portion.
The mixture was stirred for 1 h at room temperature and then filtered
through a pad of silica gel. The solid was washed using hexane/ethyl
acetate (1/1) as the eluent, and the filtrate was concentrated and purified
by silica gel column chromatography, using 5% ethyl acetate in hexane as
the eluent, to afford the title compound A3 (96% yield) as a colorless oil:
Synthesis of Compound C1 by Wittig Reaction. This com-
pound was obtained using the procedure described for B1.
DIBAL-H Reduction of α,β-Unsaturated Ester C1 to C2. C2 was
synthesized using the procedure described for the synthesis of
compound A2.
1
Rf = 0.5 (3% ethyl acetate in hexane); H NMR (400 MHz; CDCl3)
δ 7.54 (2H, dt, J =7.9, 1.1 Hz), 7.26 (1H, t, J = 7.6 Hz), 7.09 (1H, dt, J =
7.7, 1.5 Hz), 6.80 (1H, d, J = 15.8 Hz), 6.22 (1H, td, J = 15.8, 5.6 Hz),
4.12 (2H, dd, J = 5.9, 1.4 Hz), 3.41 (3H, s); 13C NMR (100 MHz;
CDCl3) δ 136.8, 133.1, 131.3, 129.2, 129.1, 127.7, 127.3, 123.8, 73.1,
58.3; HRMS (EI, TOF) calcd for C10H11BrO [M]+ 225.9993, found
225.9984; IR (neat, cm−1) 3055, 1440, 1113.
(E)-1-Bromo-2-(3-methoxy-2-methylprop-1-en-1-yl)benzene
(C3). C3 was synthesized using the procedure described for the syn-
thesis of compound A3. Chromatographic purification (5% ethyl acetate
in hexane) afforded compound C3 (92% yield) as a colorless oil: Rf =
0.5 (5% ethyl acetate in hexane); 1H NMR (400 MHz; CDCl3) δ 7.57
(1H, d, J = 7.8 Hz), 7.28−7.24 (2H, m), 7.12−7.06 (1H, m), 6.52
(1H, s), 4.01 (2H, s), 3.40 (3H, s), 1.76 (3H, d, J = 1.3 Hz).); 13C NMR
(100 MHz; CDCl3) δ 137.8, 136.6, 132.6, 130.9, 128.3, 126.9, 126.5,
124.3, 78.0, 57.9, 15.2; HRMS (EI, TOF) calcd for C11H13BrO [M]+
240.0150, found 240.0147; IR (neat, cm−1) 3066, 2222, 1491.
(E)-1-(3-Methoxy-2-methylprop-1-en-1-yl)-2-(phenylethynyl)-
benzene (1c). This compound was obtained by following the pro-
cedure described for the synthesis of 1a. Chromatographic purification
(5% ethyl acetate in hexane) afforded compound 1c (94% yield) as a
brown oil: Rf = 0.6 (5% ethyl acetate in hexane); 1H NMR (400 MHz;
CDCl3) δ 7.60 (1H, dd, J = 7.5, 0.9 Hz), 7.57−7.54 (2H, m), 7.40−7.32
(5H, m), 7.26 (1H, dt, J = 7.4, 1.4 Hz), 6.90 (1H, s), 4.09 (2H, d, J = 0.8
Hz), 3.44 (3H, s), 1.91 (3H, d, J = 1.2 Hz); 13C NMR (100 MHz;
CDCl3) δ 139.6, 136.3, 132.2, 131.6 (2C), 129.1, 128.5 (2C), 128.3,
128.0, 126.6, 126.0, 123.6, 123.0, 93.9, 88.6, 78.6, 57.7, 15.6; HRMS
(EI, TOF) calcd for C19H18O [M]+ 262.1358, found 262.1344; IR
(neat, cm−1) 3071, 2220, 1469, 981.
(E)-1-(3-Methoxyprop-1-en-1-yl)-2-(phenylethynyl)benzene
(1a). A suspension of aryl bromide (4.5 mmol), PdCl2(PhCN)2
(0.23 mmol), and Cu(I) iodide (0.23 mmol) in 20 mL of triethylamine
was degassed three times with the freeze/pump/thaw technique in a
flame-dried round-bottom flask. Once the reaction mixture was com-
pletely thawed and the atmosphere replaced with argon, tri-tert-
butylphosphine (0.45 mmol in a 10% solution of toluene) was added,
immediately followed by 1.2 equiv of phenylacetylene (5.4 mmol) using
a syringe. The mixture was allowed to react for 8 h and monitored by
TLC. After total consumption of the aryl bromide, the reaction mixture
was filtered through Celite and extracted with DCM (3 × 30 mL). The
organic layer was washed with a saturated solution of ammonium
chloride and water and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure. Chromatographic purification (5%
ethyl acetate in hexane) afforded compound 1a (95% yield) as a brown
oil: Rf = 0.6 (5% ethyl acetate in hexane); 1H NMR (400 MHz; CDCl3)
δ 7.61−7.54 (4H, m), 7.41−7.36 (3H, m), 7.31 (1H, t, J = 7.6 Hz),
7.26−7.20 (2H, m), 6.41 (1H, td, J = 16.0, 6.0 Hz), 4.18 (2H, dd, J = 6.0,
1.1 Hz), 3.43 (3H, s); 13C NMR (100 MHz; CDCl3) δ 138.3, 132.7,
131.7 (2C), 130.7, 128.7, 128.6, 128.5 (2C), 128.1, 127.5, 125.4, 123.5,
122.1, 94.2, 88.0, 73.4, 58.2; HRMS (EI, TOF) calcd for C18H16O [M]+
248.1201, found 248.1195; IR (neat, cm−1) 3055, 2214, 1489, 965.
Synthesis of Compound B1 by Wittig Reaction. To a sus-
pension of sodium hydride (60% dispersion in mineral oil, 8 mmol) in
dry THF (200 mL) was added dropwise triethyl phosphonoacetate
(4 mmol) at 0 °C under an argon atmosphere. After 30 min,
2′-bromoacetophenone (5.4 mmol) was added to the reaction mixture,
which was then warmed to room temperature and stirred for 8 h. A
saturated aqueous ammonium chloride solution (20 mL) was then
(E)-3-(2-(Phenylethynyl)phenyl)prop-2-en-1-ol (D1). This
compound was obtained by following the procedure described for the
synthesis of 1a. Chromatographic purification (5% ethyl acetate in
hexane) afforded compound 1C (96% yield) as a brown solid: mp
1
59 °C; Rf = 0.6 (5% ethyl acetate in hexane); H NMR (600 MHz;
CDCl3) δ 7.58−7.53 (4H, m), 7.38−7.34 (3H, m), 7.30 (1H, t, J = 7.4 Hz),
7.25−7.22 (1H, m), 7.20 (1H, d, J = 15.9 Hz), 6.48 (1H, td, J = 15.9,
5.7 Hz), 4.38 (2H, dd, J = 5.7, 1.3 Hz), 1.73 (1H, bs); 13C NMR (150 MHz;
CDCl3) δ 138.2, 132.6, 131.6 (2C), 130.8, 128.8, 128.6, 128.5 (2C), 128.4,
127.3, 125.2, 123.3, 121.9, 94.1, 87.9, 63.7; HRMS (EI, TOF) calcd for
C17H14O [M]+234.1045, found 234.1039; IR (neat, cm−1) 3325 (b), 3056,
2856, 1491.
7499
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(E)-1-(3-Iodoprop-1-en-1-yl)-2-(phenylethynyl)benzene (D2).
A DCM solution of compound D1 (0.5 g, 2.13 mmol) was cooled to
0 °C. Triphenylphosphine (0.61 g, 2.35 mmol), iodine (0.59 g, 2.35 mmol),
and imidazole (0.29 g, 4.26 mmol) were slowly added to this solution.
After it was stirred at 0 °C for 2 h, the reaction mixture was quenched
with water and extracted with ethyl acetate (50 mL). The extract was
washed with brine solution, dried over MgSO4, and concentrated under
reduced pressure. The residue was eluted through a silica column to
afford compound D2 (75%) as a dark brown solid: mp 63 °C; Rf = 0.3
94−95 °C; Rf = 0.6 (in hexane); 1H NMR (600 MHz; CDCl3) δ 7.73
(1H, d, J = 7.6 Hz), 7.53−7.50 (3H, m), 7.42 (2H, t, J = 7.6 Hz), 7.35
(1H, t, J = 7.5 Hz), 7.32 (1H, t, J = 7.4 Hz), 7.26 (1H, dt, J = 7.3, 0.8 Hz),
6.87 (1H, dd, J = 18.1, 11.7 Hz), 5.89 (1H, dd, J = 18.1, 0.5 Hz), 5.54
(1H, d, J = 11.7 Hz), 3.82 (2H, s); 13C NMR (150 MHz; CDCl3) δ
144.8, 143.7, 143.0, 137.3, 136.3, 131.3, 129.0 (2C), 128.5 (2C), 127.5,
126.6, 125.2, 123.9, 121.0, 118.1, 41.3; HRMS (EI, TOF) calcd for
C17H14 [M]+ 218.1096, found 218.1090; IR (neat, cm−1) 3021, 2922,
1702, 1598, 1384.
1
(hexane); H NMR (400 MHz; CDCl3) δ 7.60−7.52 (4H, m), 7.42−
Procedure for Diels−Alder Reaction of 4d with N-Phenyl-
maleimide. 2,10a-Diphenyl-4,10,10a,10b-tetrahydroindeno[2,1-e]-
isoindole-1,3(2H,3aH)-dione (6d). A solution of 1d (0.34 mmol) in
toluene was brought to reflux. A solution of tributyltin hydride (1.2
equiv) and AIBN (0.5 equiv) in toluene was added dropwise to the
reaction mixture. The resulting mixture was refluxed for 12 h. Toluene
was evaporated in vacuo, and the reaction mixture was dissolved in
20 mL of DCM and washed with a 2 M HCl solution to accomplish
protodestannylation. DCM was then evaporated, and the residue was
dissolved in 2 mL of toluene. The reaction mixture was transferred to a
pressure tube, and N-phenylmaleimide (1 equiv) was added to it. The
mixture was heated to 140 °C for 12 h. Toluene was removed in vacuo,
and the residue was purified by column chromatography (25% ethyl
acetate in hexanes) to afford 6d (93%) as a white solid: mp 220−221 °C;
Rf = 0.6 (5% ethyl acetate in hexane); 1H NMR (600 MHz; CDCl3) δ
7.57−7.55 (1H m), 7.40 (2H, t, J = 7.4 Hz), 7.35−7.30 (5H, m), 7.25−
7.20 (4H, m), 7.16−7.14 (2H, m), 6.46 (1H, dd, J = 7.5, 3.4 Hz), 4.85
(1H, d, H = 17.2 Hz), 4.15 (1H, d, J = 8.5 Hz), 3.23 (1H, t, J = 8.13 Hz),
3.051 (1H, d, J = 17.2 Hz), 2.75−2.71 (1H, m), 2.14 (1H, dq, J = 8.6, 3.4
Hz); 13C NMR (150 MHz; CDCl3) δ 179.0, 176.9, 149.9, 145.3, 144.3,
138.6, 13.0, 129.3, 129.1 (4C), 128.7, 16.9, 126.8, 126.6 (2C), 125.8,
125.6 (2C), 120.2, 114.6, 52.3, 47.5, 45.2, 40.2, 25.8; HRMS (EI, TOF)
calcd for C27H21NO2[M]+ 391.1572, found 391.1565; IR (neat, cm−1)
3020, 1772, 1700, 1493, 1348.
7.37 (3H, m), 7.31 (1H, dt, J = 7.6, 1.5 Hz), 7.24 (1H, dt, J = 7.5, 1.4 Hz),
7.18 (1H, d, J = 15.6 Hz), 6.57 (1H, td, J = 15.6, 8.2 Hz), 4.18 (2H, dd,
J = 8.2, 1.0 Hz); 13C NMR (100 MHz; CDCl3) δ 137.4, 132.9, 131.8
(2C), 131.2, 128.9, 128.7 (2C), 128.6 (2C), 128.0, 125.5, 123.4, 122.3,
94.6, 87.7, 7.0; HRMS (EI, TOF) calcd for C17H13I [M]+ 344.0062,
found 344.0054; IR (neat, cm−1) 3015, 2923, 1490, 1135, 958.
(E)-Ethyl(3-(2-(phenylethynyl)phenyl)allyl)sulfane (1d). A sol-
ution of compound D2 (2.13 mmol) in acetonitrile/THF (5/1 mixture)
was cooled to 0 °C. DBU (2.35 mmol) was added to this solution. Then
ethanethiol (2.35 mmol) was added slowly to the reaction mixture. The
reaction mixture was stirred at 0 °C for 15 min. The reaction mixture
was then quenched with water and extracted with ethyl acetate (50 mL).
The extract was washed with brine solution, dried over MgSO4, and
concentrated under reduced pressure. Chromatographic purification
(5% ethyl acetate in hexane) afforded compound 3d (89% yield) as a
yellow oil: Rf = 0.7 (5% ethyl acetate in hexane); 1H NMR (400 MHz;
CDCl3) δ 7.58−7.52 (4H, m), 7.40−7.36 (3H, m), 7.31 (1H, t, J =
7.5 Hz), 7.23 (1H, t, J = 7.3 Hz), 7.02 (1H, d, J = 15.7 Hz), 6.34−6.26
(1H, m), 3.38 (2H, d, J = 7.4 Hz), 2.56 (2H, q, J = 7.2 Hz), 1.27 (3H, t,
J = 7.2 Hz).13C NMR (100 MHz; CDCl3) δ 138.5, 132.7, 131.7 (2C),
130.2, 127.7, 128.6 (3C), 128.2, 127.3, 125.3, 123.5, 94.2, 88.1, 34.2,
24.7, 14.7; HRMS (EI, TOF) calcd for C19H18S [M]+ 278.1129, found
278.1123; IR (neat, cm−1) 3022, 2885, 14780, 1002, 848.
Procedure for Stille Coupling. 1-(4-Methoxyphenyl)-3-methyl-
2-phenylnaphthalene (8c). A solution of 1c (0.34 mmol) in toluene
was brought to reflux. A solution of tributyltin hydride (1.2 equiv) and
AIBN (0.5 equiv) in toluene was added dropwise to the refluxing
solution of 1c. The reaction mixture was allowed to reflux for 12 h.
Toluene was evaporated under vacuum. A two-necked flask was charged
with lithium bromide (2.04 mmol) and flame-dried under high vacuum.
Upon cooling, tetrakis(triphenylphosphine)palladium(0) (0.034 mmol)
and CuCl (1.7 mmol) were added, and the mixture was degassed (4×)
under high vacuum with an argon purge. Dry DMF (4.0 mL) was
introduced with concomitant stirring, followed by the addition of
4-iodoanisole (0.35 mmol) and the tributyltin reaction mixture. The
resulting mixture was rigorously degassed (4×) by the freeze−pump−
thaw method using liquid nitrogen under an argon atmosphere. The
reaction mixture was stirred at room temperature for 1 h and then heated
to 110 °C for 12 h. Following completion of the coupling as monitored
by TLC, the reaction mixture was cooled, diluted with Et2O, and washed
with brine. The aqueous layer was further extracted with Et2O (3×), and
the combined organic layers were washed with water (2 × 40 mL) and
brine (2 × 40 mL) and dried over Na2SO4. Concentration under vacuum
afforded a residue that was purified by column chromatography (Si-gel/
10% ethyl acetate in hexane) to afford 8c (52%) as a yellow solid: mp
161−162 °C; Rf = 0.6 (in hexane); 1H NMR (600 MHz; CDCl3) δ 7.84
(1H, d, J = 8.2 Hz), 7.76 (1H, s), 7.52 (1H, d, J = 8.5 Hz), 7.47−7.44
(1H, m), 7.34−7.31 (1H, m), 7.22−7.19 (2H, m), 7.15−7.14 (1H, m),
7.05−7.01 (4H, m), 6.77−6.75 (2H, m), 3.77 (3H, s), 2.26 (3H, s); 13C
NMR (150 MHz; CDCl3) δ 158.1, 141.0, 140.3, 138.5,134.7, 133.2,
132.2 (2C), 131.9, 131.8, 130.3 (2C), 127.8 (2C), 127.5, 127.3, 127.1,
126.3, 125.9, 125.4, 113.1 (2C), 55.3, 22.1; HRMS (APCI, TOF) calcd
for C24H20O[M]+ 324.1514, found 324.1509; IR (neat, cm−1) 3031,
2855, 1150, 972.
General Procedure for AIBN/Bu3SnH-Mediated Cyclizations.
The starting enyne (0.34 mmol) was degassed in 4 mL of toluene and
heated to reflux. Two separate solutions of AIBN (0.5 equiv) and
Bu3SnH (1.2 equiv) each in 3 mL of toluene were added using a syringe
pump through the top of a condenser over the course of 4 h into the
refluxing solution. The reaction mixture was stirred at reflux for 12 h.
After completion, as confirmed by TLC, the solvent was evaporated and
the product was dissolved in 20 mL of DCM and washed with a 2 M HCl
solution to accomplish protodestannylation. The products were purified
on silica gel using a gradient of hexanes followed by ethyl acetate/hexane
eluent.
2-Phenylnaphthalene (3a). Chromatographic purification (hexane)
afforded compound 3a (75% yield) as a white solid: mp 105−106 °C;
Rf = 0.5 (hexane); 1H NMR (600 MHz; CDCl3) δ 8.06 (1H, s), 7.94−
7.88 (3H, m), 7.78−7.74 (3H, m), 7.54−7.50 (4H, m), 7.40 (1H, t, J =
7.3 Hz); 13C NMR (150 MHz; CDCl3) δ 141.3, 38.8, 133.8, 132.8, 129.1
(2C), 128.6, 128.4, 127.8, 127.6 (2C), 127.5, 126.5, 126.1, 126.0, 125.8;
HRMS (EI, TOF) calcd for C16H12 [M]+ 204.0939, found 204.0938; IR
(neat, cm−1) 3056, 2921, 1947, 1453.
1-Methyl-3-phenylnaphthalene (3b). Chromatographic purifica-
tion (hexane) afforded compound 3b (92% yield) as a white solid: mp
1
44−45 °C; Rf = 0.6 (in hexane); H NMR (400 MHz; CDCl3) δ 8.
10−8.06 (1H, m), 7.98−7.95 (2H, m), 7.81−7.78 (2H, m), 7.68 (1H, s),
7.61−7.53 (4H, m), 7.46−7.42(1H, m), 2.82 (3H, s); 13C NMR (100
MHz; CDCl3) δ 141.4, 138.4, 135.0, 134.1, 132.0, 129.0 (3C), 127.6
(2C), 127.5, 126.5, 126.2, 126.0, 124.5, 124.2, 19.7; HRMS (EI, TOF)
calcd for C17H14 [M]+ 218.1096, found 218.1095.
2-Methyl-3-phenylnaphthalene (3c). Chromatographic purification
(hexane) afforded compound 3c (70% yield) as a colorless oil: Rf = 0.6
(in hexane); 1H NMR (600 MHz; CDCl3) δ 7.81 (2H, t, J = 7.0 Hz),
7.73 (1H, s), 7.71 (1H, s), 7.48−7.44 (5H, m), 7.43−7.38 (3H, m), 2.42
(3H, s); 13C NMR (150 MHz; CDCl3) δ 142.1, 141.2, 134.1, 133.1,
132.2, 129.5 (2C), 128.6, 128.4, 128.3 (2C), 127.8, 127 1 (2C), 126.1,
125.6, 21.3; HRMS (EI, TOF) calcd for C17H14 [M]+ 218.1096, found
218.1092.
1-Iodo-3-methyl-2-phenylnaphthalene (9c). A solution of 1c
(0.34 mmol) in toluene was brought to reflux. A solution of tributyltin
hydride (1.2 equiv) and AIBN (0.5 equiv) in toluene was added
dropwise to the refluxing solution of 1c. The reaction mixture was
refluxed for 12 h. Toluene was evaporated under vacuum, and the
reaction mixture was dissolved in 2 mL of dichloromethane. Iodine
2-Phenyl-3-vinyl-1H-indene (4d). Chromatographic purification
(hexane) afforded compound 4d (69% yield) as a yellow solid: mp
7500
dx.doi.org/10.1021/jo5012043 | J. Org. Chem. 2014, 79, 7491−7501

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Article
(0.51 mmol) was added and the reaction mixture stirred at room
temperature for 8 h. The reaction mixture was quenched with a saturated
aqueous solution of sodium bisulfite. The aqueous layer was extracted
with dichloromethane (4×), and the combined organic layer was dried
over sodium sulfate and concentrated. Chromatographic purification
(hexane) afforded compound 9c (92% yield) as a white solid: mp
95−96 °C; Rf = 0.4 (in hexane); 1H NMR (600 MHz; CDCl3) δ 8.23
(1H, dd, J = 8.3, 0.7 Hz), 7.75−7.73 (1H, m). 7.69 (1H, s), 7.55−7.49
(4H, m), 7.46−7.43 (1H, m), 7.19−77.18 (2H, m), 2.22 (3H, d, J = 0.6
Hz); 13C NMR (150 MHz; CDCl3) δ 147.3, 146.1, 135.3, 133.9 (2C),
133.5, 129.3 (2C), 128.9, 128.6 (2C), 127.7 (2C), 127.3, 126.8, 106.2,
23.1; HRMS (EI, TOF) calcd for C19H13I[M]+ 344.0062, found
344.0055; IR (neat, cm−1) 3021, 2861, 1141, 958.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, tables, and a CIF file giving 1H NMR, 13C NMR,
and 2D NMR spectra for all of the compounds prepared, X-ray
crystallographic data for 6d, and computational details and
Cartesian coordinates for all calculated structures. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for I.V.A.: alabugin@chem.fsu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
I.V.A. is grateful to the National Science Foundation (CHE-
1213578 and CHE-1152491) for support of the fundamental and
applied components of this research project.
REFERENCES
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