Lewis Acid-Mediated Cyclization of Allenyl Aryl Ketones

Article abstract of DOI:10.1021/acs.joc.9b01900

The cyclization of a series of nonheterocyclic allenyl aryl ketones was examined using boron trifluoride etherate and indium triflate to mediate the reaction. Yields with BF₃ were low in most instances due mainly to competitive destruction of t

Full text of DOI:10.1021/acs.joc.9b01900

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Article
Lewis Acid-mediated Cyclization of Allenyl Aryl Ketones
Mariam Zaky, Zhe Li, Timothy Morgan, François M. LeFort, Russell Jaye Boyd, and D. Jean Burnell
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01900 • Publication Date (Web): 25 Sep 2019
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Lewis Acid-mediated Cyclization of Allenyl Aryl Ketones
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Mariam Zaky, Zhe Li, Timothy D. R. Morgan, François M. LeFort, Russell J. Boyd,* and D.
Jean Burnell*
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Department of Chemistry, Dalhousie University, P. O. Box 15000, Halifax, Nova Scotia B3H
4R2, Canada
email: russell.boyd@dal.ca, jean.burnell@dal.ca
Abstract: The cyclization of a series of nonheterocyclic allenyl aryl ketones was examined using
boron trifluoride etherate and indium triflate to mediate the reaction. Yields with BF3 were low
in most instances due mainly to competitive destruction of the substrates. With In(OTf)3 there
was less decomposition, and the yields of cyclized product were much higher, but only for
substrates with electron-donating substituents. Cyclization did not occur without those
substituents. A computational study using the ωB97X-D/6-311+G(2d,p)//ωB97X-D/6-31+G(d,p)
method confirmed better stability of the -complexed substrate by indium(III) and that meta-
substituents on the phenyl ring of the substrate significantly influenced the activation barrier of
the cyclization whereas the effect of para-substituents was almost negligible. The computational
results supported the idea that the cyclization is a 4π-electrocyclization and not a 5-endo-dig ring
closure as had been proposed in the literature.
TOC graphic
.
O
BF3 Et2O
O
or
Me
In(OTf)3
Me
.
Yields 0 - 99%
X
X
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INTRODUCTION
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The acid-mediated cyclization of a divinyl ketone to yield a cyclopentenone takes place by a 4-
electrocyclic mechanism, and this transformation, known as the Nazarov reaction, has been
developed considerably over the past two decades.1,2 An aryl vinyl ketone can undergo a similar
reaction. A transient loss of aromaticity is consistent with reaction conditions that are harsher
than for a divinyl ketone.3,4 Nevertheless, cyclizations of aryl vinyl ketones and heteroaryl vinyl
ketones, especially indole vinyl ketones for which loss of aromaticity is less energetically costly,
have been reported many times and have been exploited synthetically with much success.3-6 The
Frontier group insightfully employed cationic halo-allyl aryl systems for synthesizing substituted
indenes because cyclization of these substrates requires much lower activation energies than do
the acid-mediated cyclizations of aryl vinyl ketones.4
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Allenyl vinyl ketones are more reactive substrates for Nazarov reactions than divinyl
ketones. Hashmi7 reported that some allenyl vinyl ketones underwent Nazarov cyclization during
chromatography. The oxygen-substituted allenyl vinyl ketones of Tius2 underwent spontaneous
cyclization upon formation, and even with allenyl vinyl ketones such as 1, without a strong
activating group, activation barriers for the cyclization are low, and trapping of the intermediate
cation 2 by nucleophiles or by cycloaddition to lead to, for instance, 3 is efficient (Scheme 1).8-10
Scheme 1. Tandem BF3·Et2O-Mediated Nazarov Reaction and (4+3)-Cycloaddition of an Allenyl
Vinyl Ketone8
O
F3B
Ph
O
O
.
BF3 Et2O
Ph
H
(0.3 equiv)
CH2Cl2, -78 oC
.
99%
Ph
5 min
1
2
3
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Based on the experience with allenyl vinyl ketones, cyclizations of allenyl aryl ketones
(AAKs) should be expected to be more facile than those of aryl vinyl ketones. Nagao and co-
workers11 described BF3-mediated cyclizations of some AAKs with oxygen functions on the aryl
ring. For instance, 4 gave an indanone 5 with an exocyclic methylene in good yield (Scheme 2).
Substrates without a strong -donating group on the aryl ring reacted more slowly and gave only
modest yields of cyclized product. The authors discounted the electrocyclic mechanism (Nazarov
reaction) and instead proposed a 5-endo-dig attack of aryl electrons onto the Lewis acid-
activated central allene carbon, i.e., an intramolecular electrophilic aromatic substitution. In
support of their proposal, the authors revealed that under their reaction conditions the aryl vinyl
ketone 6 gave very little cyclized product 7, which would have been the expected product of an
electrocyclization but would have been disfavored by a 5-endo-trig closure. Furthermore,
cyclization of 8, for which electrocyclization would have been impossible, was reported to take
place efficiently to yield 9, as expected for a favored 6-endo-dig ring closure.12
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Scheme 2. BF3·Et2O-Mediated Cyclizations of 4, 6, and 8
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O
O
O
.
BF3 Et2O
0 oC, 10 min
CH2Cl2
MeO
MeO
H
H
MeO
MeO
.
ref. 11
4
6
5
81%
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O
.
BF3 Et2O
MeO
MeO
MeO
MeO
reflux, 5 h
CH2Cl2
ref. 11
7
3%
.
BF3 Et2O
MeO
MeO
O
H
MeO
MeO
OH
-2 oC, 25 min
CH2Cl2
.
ref. 12
Me
53%
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Sai and Matsuhara13 showed that heating tertiary allenyl aryl alcohols to 65 °C in hexane in
the presence of LiPF6 led to Nazarov-type cyclizations to provide benzofulvenes. More recently,
Miao and co-workers14 reported many examples of AAKs that cyclized merely upon heating to
160 °C in DMSO. All of their examples involved substrates with a completely substituted allene.
The reactions were not altered by the presence of a radical scavenger, but this would not
distinguish an electrocyclic closure from an ionic 5-endo-dig cyclization.
Considering the narrow range of non-heterocyclic AAK substrates for which the acid-
mediated cyclization has been reported, it was important to reassess the cyclizations of simple
AAKs and to examine these cyclizations computationally.
RESULTS AND DISCUSSION
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Preparation of allenyl aryl ketones (AAKs). AAKs bearing a methyl group  to the ketone
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were chosen because allenyl vinyl ketones without an  methyl group were found to be much
less stable.10 Fourteen substrates were prepared from variously substituted aromatic aldehydes,
as illustrated for 10 to AAK 11b in Scheme 3. Addition of an allenylstannane to an aromatic
aldehyde was a convenient method for producing allenyl aryl alcohols,15 even though in many
instances the yields were modest.16 This was followed by oxidation of the secondary alcohol with
2-iodoxybenzoic acid (IBX) in DMSO.17 The oxidation by IBX of two substrates containing
thioether groups took place without observable oxidation at sulfur.18 4-Methoxybenzaldehyde
was recovered unchanged upon treatment with the allenylstannane under various conditions, and
this aldehyde also resisted attack by the corresponding organomagnesium reagent. However, it
was curious that more oxygenated aldehydes did react with the allenylstannane.
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Scheme 3. Preparation of AAK 11b
Br
O
OH
O
Me
SnCl2, NaI
Me
Me
IBX
H
DMF
51%
DMSO
67%
.
.
10
11a
11b
Lewis acid-mediated cyclization. Nagao and coworkers11,12 had used BF3 etherate to induce
cyclization with their substrates. Allenyl vinyl ketones react within a few minutes at -78 °C using
the same Lewis acid,8-10 but AAK 11b with BF3 etherate in CH2Cl2 remained largely unreacted
(by TLC) after an hour at -78 °C. At 0 °C cyclized product 11c was produced along with a minor
amount of 11d, in which the exocyclic double bond had isomerized into the five-membered ring.
However, the amount of decomposed material from the reaction was about equal to the amount
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of cyclized product. Variations in time and temperature did not appear to reduce the proportion
of decomposed material, and so the reactions of AAKs 11b-23b mediated by BF3 etherate were
run at 0 °C with TLC being used to monitor the disappearance of the AAK. The 3-methoxy AAK
19b cyclized relatively quickly, and a better yield of cyclized product was obtained from a
reaction at -78 °C. The results are shown in Scheme 4. Yields were generally poor, with two
exceptions, AAK 20b cyclized to 20c smoothly, a result similar to Nagao’s cyclization of 4 to 5
in Scheme 2, and the 2-naphthyl AAK 24b gave 24c quantitatively. Both AAKs bearing
trifluoromethyl substituents, 16b and 17b, gave no cyclized product.
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Two cyclized products, 13c and 13e, were obtained in a ratio of almost 1:1 from the 3-
methyl AAK 13b, which indicated that formation of the new C-C bond was not inhibited by a
steric interaction with an ortho methyl substituent. Indeed, AAK 15b, which inevitably presents
an ortho tert-butyl group, cyclized to 15c in a yield that was not significantly lower than the
cyclization of 13b. The 3-methoxy AAK 19b also provided regiochemically different cyclization
products 19d and 19f, but in this instance the ratio was 4:1 favoring C-C bond formation para to
the methoxy group. Regiochemical alternatives were possible for AAK 20b but only 20c was
detected. As with the cyclization of 11b, many cyclization products were mixtures with some of
the material having had the exocyclic double bond isomerized into the ring. The products from
AAKs 19b and 23b were entirely isomerized. Calculations showed that double bond
isomerization should be favored. The Gibbs energy of 11d is 3.8 kcal/mol lower than of 11c, and
19d is 2.9 kcal/mol lower than 19c. When the initial products of cyclization from AAK 12b, a
6:1 mixture of 12c and 12d, and from AAK 14b, a 7:1 mixture of 14c and 14d, were re-subjected
to the Lewis acid for 1 hour, 12d and 14d were the only cyclized products recovered, but
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decomposition was evident, too. Under the same conditions, pure 18c returned a 1:1 mixture of
18c and 18d.
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Cyclization of AAK 19b was tested with other Lewis acids. The addition of TiCl4, SnCl4
and FeCl3 at 0 °C led merely to the destruction of the AAK, but indium triflate, which West and
coworkers19 had explored as a catalyst to cyclize an oxazolidinone-substituted aryl vinyl ketone,
led to a much improved yield of cyclized product. The composition of that product, a 4:1 mixture
of 19d and 19f, was the same as with BF3 etherate. In(OTf)3 was employed with many of the
other AAKs at room temperature (Scheme 4). The yield of 22c improved considerably, but
among the phenyl AAKs, the results were mixed. With BF3 etherate the yields of cyclized
products from AAKs 11b, 13b, 14b, and 18b had been modest. The yield from 13b with
In(OTf)3 more than doubled relative to BF3 etherate, but 11b, 14b and 18b did not cyclize at all,
and some starting AAK was recovered. Exposure to In(OTf)3 decomposed the AAKs more
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Scheme 4. Cyclization of AAKs 11b-24b, with BF3 etherate and with In(OTf)3
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8
O
O
O
7
4
2
5
7
4
Me
6
5
3
4
6
5
Me
Me
+
.
9
Me
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c e
,
b
d f
,
o
.
.
.
.
11b
11b
12b
13b
13b
14b
14b
15b
16b
17b
18b
18b
19b
19b
20b
21b
21b
11c d
+ (7:1)
BF3 Et2O, 0 C, 1 h
51%
11c d
In(OTf)3,1 equiv, rt, 72 h
+
0%
14%
34%
o
12c d
7-Me (6:1)
2-Me
3-Me
3-Me
4-Me
4-Me
BF3 Et2O, 0 C, 1 h
+
o
13c e
+ 6- & 4-Me (1:1.2)
BF3 Et2O, 0 C, 1 h
13c,d e,f
6- & 4-Me (1:1) 72%
In(OTf)3,1 equiv, rt, 4.5 h
+
o
.
14c d
BF3 Et2O, 0 C, 2 h
+
5-Me (7:1)
33%
0%
14c d
In(OTf)3,1 equiv, rt, 4 h
+
5-Me
t
o
t
.
.
.
.
15c
3,5-di- Bu
3-CF3
BF3 Et2O, 0 C, 1.5 h
4,6-di- Bu
31%
0%
o
16c d
BF3 Et2O, 0 C, 1 h
+
4- or6-CF3
5-CF3
o
17c d
4-CF3
BF3 Et2O, 0 C, 1 h
+
0%
18c
5-SMe
4-SMe
4-SMe
3-OMe
3-OMe
BF3 Et2O, rt, 2.5 h
26%
0%
18c d
In(OTf)3,1 equiv, rt, 16 h
+
5-SMe
o
.
19d f
+ 6- & 4-OMe (4:1)
BF3 Et2O, -78 C, 20 min
32%
95%
90%
35%
85%
In(OTf)3,1 equiv, 0 oC, 1.5 h
+ 6- & 4-OMe (4:1)
5,6-OCH2O-
19d f
o
.
.
20c
3,4-OCH2O- BF3 Et2O, 0 C, 45 min
o
21c d
3,4,5-tri-OMe BF3 Et2O, 0 C, 1 h
+
4,5,6-tri-OMe (1:3)
4,5,6-tri-OMe (1:2)
In(OTf)3,0.1 equiv, rt, 1 h
21c d
3,4,5-tri-OMe
+
O
o
.
O
BF3 Et2O, 0 C, 1.5 h
50%
Me
In(OTf)3,0.7 equiv, rt, 5 h 84%
Me
.
22c
22b
O
O
Me
o
.
36%
BF3 Et2O, 0 C, 3 h
Me
.
Me
23b
23d
O
O
Me
o
.
Me
BF3 Et2O, 0 C, 45 min 99%
.
24b
24c
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slowly than did BF3 etherate. Finally, the trimethoxy AAK 21b cyclized efficiently with
In(OTf)3, even with 0.1 equiv of In(OTf)3, whereas with BF3 etherate the yield of cyclized
product had been very poor. The phenyl-based AAKs that cyclized with In(OTf)3 possessed a π-
donor at C-3 of the phenyl ring, and those that did not did not cyclize.
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Attempts to intercept the cationic intermediate. An attractive feature of allenyl vinyl ketones
is that their Nazarov reactions can be interrupted by the addition of nucleophiles or by
cycloaddition.8-10 AAKs 11b, 17b, 20b, and 24b were treated with BF3 etherate at 0 °C in the
presence of a ten-fold, or more, excess of 2,3-dimethylbutadiene. No cycloaddition product was
detected, but 11c, 20c and 24c were obtained. Some of the starting AAK 17b was recovered. It
was obvious that deprotonation of the cyclized product was much faster than cycloaddition.
Thus, AAK 25b, which could not re-aromatize if cyclization did occur, was tested with BF3
etherate in the presence of excess 2,3-dimethylbutadiene, but only the destruction of the AAK
was observed.
Me
O
Me
.
Me
Me
25b
Computational study. In order to better understand the course of the cyclization reactions of
simple AAKs, attention turned to a computational examination. The Gaussian 09 software
package was used.20 Stationary points were fully optimized in their ground states using the
dispersion-corrected ωB97X-D density functional21 with the 6-31+G(d,p) extended basis set.
This level of density functional theory had been used successfully in related studies.22 The
LanL2DZ basis set was used for In.23 Minima and first-order saddle points were characterized by
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their number of imaginary frequencies following normal-mode vibrational analysis, i.e., 0 and 1,
respectively. For many systems, the intrinsic reaction coordinate (IRC) method was used to
connect transition states to the starting material and product minima.24 Single point energies were
determined using ωB97X-D/6-311+G(2d,p) with the optimized geometries. Solvation energies in
CH2Cl2 solution were calculated using the SMD continuum solvation model,25 and Gibbs
energies were obtained from the single-point energies in solution with corrections from gas-
phase frequency calculations. The charges were calculated by the NBO population analysis in
Gaussian 09.26 Geometries and thermodynamic data were obtained from calculations carried out
in the gas phase at 298.15 K and 1.0 atm.
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Computational evaluation of BF3- versus InCl3-mediated cyclization. The cyclization
mediated by BF3 was compared with that mediated by InCl3 using the simplest AAK substrate
26. InCl3 was chosen to approximate In(OTf)3 to reduce the computational cost. Figure 1 shows
the Gibbs energy reaction profiles for the cyclizations. The initial complex with InCl3 (27a) was
lower in energy than the complex with BF3 (27b), and similarly the complex following
cyclization was also better stabilized by InCl3 (28a) than by BF3 (28b). However, the activation
barrier for the cyclization with InCl3 was higher than that with BF3 by 3.5 kcal/mol, which
agreed with the observation that In(OTf)3-mediated cyclizations required higher temperatures
and longer times. It might be hypothesized that an In(OTf)3-mediated cyclization could take
+
place following loss of OTf- from the initial complex. This was modeled using cationic InCl2 in
+
the place of InCl3. The activation barrier for cyclization with InCl2 was only 1.8 kcal/mol higher
+
than that of the reaction with InCl3, but formation of the initial complex 27c with InCl2 was very
endothermic. Therefore, decomplexation of the indium before cyclization was unlikely.
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Indium(III) can behave as a -acid with a carbon-carbon -bond, and there are now many
examples of catalysis by indium(III) proceeding by this mechanism.27 Cyclization of 26 via the
indium(III) -complex 27d was examined computationally (Figure 1). The activation barrier for
cyclization from 27d to 28d was 1.7 kcal/mol lower than for cyclization of the -coordinated
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complex 27b to 28b. However, the -complex 27d was only 2.0 kcal/mol lower in energy than
uncomplexed 26. Barriers to complexation are very low, and the formation of 27d would
obviously be reversible. Therefore, the activation energy for the cyclization via 27d to 28d
should be calculated from the -complex 27b, which was 17.6 kcal/mol lower in energy than the
-complex 27d, and so the activation barrier for the InCl3-mediated cyclization by -
complexation would be 43.0 kcal/mol. This is much higher than the activation barrier of 27.1
kcal/mol for the cyclization of the -complex 27b to 28b.
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27c 28c ‡
[
-
]
InCl2
O
+55.0
O
InCl2
6
7
8
.
28.9
H
28c
9
28c
+36.3
27c
O
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O
.
27c
+26.1
27d 28d ‡
+23.4
[
-
]
InCl3
27d
27a 28a ‡
[
-
]
O
H
InCl3
+16.2
25.4
28d
27b 28b ‡
[
-
]
28d
.
O BF3
+7.5
+5.6
23.6
28a
26
0.0
27d
-2.0
27a
+1.6
H
28a
BF3
28b
-8.7
27.1
O
-7.4
O
InCl3
27b
-19.6
.
InCl3
27a
O
H
28b
.
27b
reaction progress
Figure 1. Gibbs energy profile for the cyclization of AAK 26 mediated by BF3 and InCl3. Gibbs
energies in kcal/mol (ωB97X-D/6-311+G(2d,p)//ωB97X-D/6-31+G(d,p) using SMD-PCM:
CH2Cl2) are in italics.
Computational examination of electrocyclic versus ionic cyclizations. The second objective
was to determine the nature of the BF3-mediated cyclization of AAKs by examining the
transition states of the cyclizations of various substrates. Nagao and coworkers11,12 had surmised,
based on the examples shown in Scheme 2, that cyclizations of AAKs are 5-endo-dig ring
closures (ionic, electrophilic substitution reactions). We compared computationally cyclizations
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of the simplest AAK 26 and the simplest AAK 11b for which we had experimental data with
substrates 29a,b, 30a,b, 31a,b, and 32 (Figure 2). Substrates 29a and 29b are aryl vinyl ketones.
Their cyclizations would either be 4π-electrocyclizations (Nazarov reactions) or highly
disfavored ionic 5-endo-trig ring closures. Substrates 30a,b are divinyl ketones, traditional
substrates for Nazarov reactions. Substrates 31a,b cannot cyclize by the 4π-electrocyclic
mechanism and so cyclization would be by an ionic 6-endo-dig ring closure. Similarly, 32 could
only cyclize by an ionic mechanism, in this case a 5-endo-dig ring closure. Salient data on the
nine transition states are given in Table 1.
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26
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For the three pairs of substrates that might cyclize by an electrocyclic mechanism, those
with methyl-substitution on the allene 11b, 29b and 30b had lower activation barriers, by
approximately 3 kcal/mol, relative to the corresponding unmethylated compounds. This was not
related to a difference in the relative position of the BF3 in the methylated and unmethylated
compounds since the geometries were very similar. (See the Supporting Information for some
illustrations.) The difference may be attributable to the greater stabilization of the developing
charge in the immediate, cationic product of cyclization. Methylated 31b, which can only cyclize
by a 6-endo-dig ring closure, had an activation barrier that was 1.4 kcal/mol higher than that of
unmethylated 31a. The modestly electron-donating methyl group on the enone moiety in 31b
might slightly retard an ionic process in which electron density flows towards the enone.
The AAKs 26 and 11b had activation barriers that were approximately 5 kcal/mol lower
than those of the corresponding aryl vinyl ketones 29a,b. The effect of interrupting aromaticity
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O
O
O
6'
1'
R
R
R
6
7
.
3
2'
8
9
26
11b
29a
29b
30a
30b
R = H
R = Me
R = H
R = Me
R = H
R = Me
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O
6'
O
R
1'
2'
.
.
4
31a
31b
32
R = H
R = Me
Figure 2. Substrates for which the transition states of their cyclization were compared
computationally
Table 1. Computational data (ωB97X-D/6-311+G(2d,p)//ωB97X-D/6-31+G(d,p) with SMD-PCM:
CH2Cl2) for the transition states of the BF3-mediated cyclizations of the substrates in Figure 2
Substrate ΔG‡
Incipient bond Dihedral C3,2ʹ,1ʹ,6ʹ Charge at C3 Charge at 2ʹ
(kcal/mol) (Å)
(degree)
138.4
26
23.6
20.7
28.9
25.6
18.6
16.0
21.2
22.6
35.0
1.95
1.98
1.93
1.96
2.06
2.11
1.84
1.88
1.85
+0.07
+0.08
-0.40
-0.39
-0.41
-0.40
+0.08a
+0.10a
+0.11
-0.31
-0.29
-0.30
-0.28
-0.22
-0.20
-0.35
-0.33
-0.36
11b
29a
29b
30a
30b
31a
31b
32
136.9
137.5
137.2
142.4
142.5
98.8a
98.0a
112.7
a
C4 instead of C3 for this substrate
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was evident comparing 29a,b with 30a,b. The activation barriers of the nonaromatic substrates
30a,b were close to 10 kcal/mol lower in energy than for the aromatic substrates 29a,b. Thus, the
activation barriers for the AAKs were about midway between the barriers for aryl vinyl ketones
and divinyl ketones. Whereas the 6-endo-dig ring closures of 31a,b had activation barriers that
were not dissimilar to those of the AAKs 26 and 11b, the activation barrier of the 5-endo-dig
ring closure of 32 was very much higher than the activation barriers for 26 and 11b.
Geometries of the transition state structures were also consistent with the ring closure of
AAKs being electrocyclic (Nazarov reaction) rather than ionic. The lengths of the incipient
bonds for 26, 11b, 29a,b, and 30a,b were similar, roughly 2.0 Å; the least reactive, 29a,b were
slightly shorter, and the most reactive, 30a,b, were slightly longer. In contrast, the incipient bond
lengths for 31a,b and 32 were very similar, 1.84-1.88 Å, even though these transition states
resulted in products with six- and five-membered rings, respectively. However, the most
important differences between the electrocyclic reactions and the ionic ones was the position of
the phenyl ring relative to the allene or vinyl. For the electrocyclic reactions the dihedral angle
from carbons 2ʹ,1ʹ,and 6ʹ to the reacting carbon of the allene or vinyl was between 136.9° and
142.5°. For the ionic reactions the reacting carbon of the allene was close to perpendicular to the
phenyl. For the 6-endo-dig ring closures of 31a,b the corresponding dihedral angle was 98°, and
for the 5-endo-dig ring closure of 32 it was 112.7°.28
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The charges at the reacting carbons at the transitions states were examined. The charge at
the reacting carbon of the ring was negative and similar in every instance, with the charges at
that carbon being smallest for the divinyl ketones 30a,b. At the reacting carbon of the allene or
vinyl there were significant differences, but these depended on whether that carbon was of an
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allene or a vinyl. For the allenes, 26, 11b, 31a, 31b and 32, the charge was smaller and positive.
For the vinyl compounds, 29a,b and 30a,b the charge was larger and negative.
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Computed substituent effects. The experimental study included AAKs with strong π-donors,
modest π-donors, and electron withdrawing substituents on the phenyl ring. Those with the
electron-withdrawing trifluoromethyl substituent did not provide any cyclized product, but for
the other substrates the rates of the BF3-mediated reactions did not appear to vary greatly.
However, the experimental results, with a significant proportion of material diverted to
unidentified reaction pathways, did not lend themselves to reliable conclusions regarding the
relative rates of cyclization. Therefore, substituent effects were explored computationally by
examining variously substituted substrates based on 26, 11b, and 32. These are shown in Figure
3 along with the most important computed data.
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O
6'
R
1'
H
.
3
2'
R'
‡
26
33
34
35
36
°
°
R, R' = H
G 23.6; dihedral 138.4
‡
R = OMe, R' = H G 20.4; dihedral 137.2
‡
°
R = CF3, R' = H G 25.7; dihedral 139.4
‡
°
R = H, R' = OMe G 24.2; dihedral 137.8
‡
°
R = H, R' = CF3 G 23.5; dihedral 138.7
O
O
6'
6'
R
R
1'
Me
1'
2'
.
.
3
3
2'
R'
R'
‡
‡
11b
19b
13b
16b
37
°
32
38
39
40
41
42
43
°
R, R' = H
G 20.7; dihedral 136.9
R, R' = H
G 35.0; dihedral 112.7
‡
‡
°
°
R = OMe, R' = H G 18.4; dihedral 136.3
R = OMe, R' = H G 31.5; dihedral 113.4
‡
‡
°
°
R = Me, R' = H
G 18.6; dihedral 136.8
R = Me, R' = H
G 33.4; dihedral 112.4
‡
‡
°
°
R = CF3, R' = H G 22.4; dihedral 137.6
R = CF3, R' = H G 37.6; dihedral 118.7
‡
‡
°
°
R = H, R' = OMe G 20.7; dihedral 133.6
R = H, R' = OMe G 34.8; dihedral 111.3
‡
‡
14b
17b
°
°
R = H, R' = Me
G 19.8; dihedral 133.9
R = H, R' = Me
G 35.9; dihedral 112.1
‡
‡
°
°
R = H, R' = CF3 G 20.2; dihedral 133.8
R = H, R' = CF3 G 39.5; dihedral 113.1
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Figure 3. AAKs studied computationally with ωB97X-D/6-311+G(2d,p)//ωB97X-D/6-31+G(d,p)
with SMD-PCM: CH2Cl2, with the activation barriers (G‡) in kcal/mol and the C3,2ʹ,1ʹ,6ʹ dihedral
angles at the transition states of their BF3-mediated cyclizations
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It was clear that the dihedral angles (C3,2ʹ,1ʹ,6ʹ) at the transition states of the cyclizations
of all of the derivatives of 26 and 11b, which would be transition states of electrocyclizations,
were similar and much larger than the corresponding dihedral angles of the derivatives of 32,
which would be ionic, 5-endo-dig ring closures. There was no correlation in either group
between the activation energy and the dihedral angle.
Just as for 26 versus 11b, the methyl-substituted allene compounds had activation barriers
that were always lower than the corresponding hydrogen-substituted AAKs. The order of the
activation barriers of the meta-substituted AAKs followed the order of electron donation, with
the methoxy-substituted AAKs 33 and 19b having the lowest activation barriers. Thus, electron
donation to the phenyl carbon that forms the new carbon-carbon bond facilitated the
electrocyclization.
Para-substitution of the AAKs did not influence the activation barriers as much as meta-
substitution, and, within the small range the ΔG‡ values, the activation barriers did not follow the
order of electron donating ability. The CF3-substituted AAK 36 had an activation barrier that was
not significantly different to that of unsubstituted AAK 26, and it was 0.7 kcal/mol lower than
the activation barrier for the methoxy-substituted AAK 35. In a similar way, the CF3-substituted
AAK 17b had an activation barrier that was slightly lower than that of methoxy-substituted AAK
37, but AAK 17b had an activation barrier that was marginally (0.4 kcal/mol) higher than that of
14b with a methyl-substituted phenyl ring.
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For the substrates based on 32, which cyclize by an ionic 5-endo-dig ring closure, those
with meta-substitution (38–40) had activation barriers that follow the order of electron donation.
The para-substituted substrates (41–43) showed a greater range of activation energies than did
the AAKs, and these ordered with electron donation, also.
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CONCLUSIONS
Except for a few examples, the BF3-mediated cyclization of simple AAKs gives, at best,
very modest yields due to destructive competing pathways. However, for some substrates indium
triflate is a superior Lewis acid. A computational examination, using InCl3 in the place of
In(OTf)3, offered a number of insights into this cyclization. Relative to BF3, In(III) better
stabilizes the complex with the AAK both before and after cyclization, which should serve to
reduce destruction of the AAK and its immediate product after cyclization, but with In(III) the
activation barrier for cyclization is higher, thus necessitating higher reaction temperatures and
longer times than the BF3-mediated cyclization. The computational data point to the cyclization
itself being a 4π-electrocyclization and not an ionic 5-endo-dig ring closure, as had been
proposed previously. A meta-substituent on the phenyl ring has a significant effect on the
activation barrier to cyclization, with electron donation by the substituent lowering the barrier. In
contrast, a para-substituent has a small effect on the activation barrier, and that effect does not
correlate with the electron donating ability of the substituent.
EXPERIMENTAL SECTION
General considerations. Anhydrous DMF, DMSO and all reagents were used as received from
commercial sources, except BF3 etherate was distilled. CH2Cl2 was distilled over calcium
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hydride, and the bulk solvents used in workup and chromatography were distilled. 2-
Iodoxybenzoic acid (IBX) was prepared as described by Frigerio et al.29 Flash chromatography
employed silica gel (40-63 μm particle size, 230-240 mesh). Melting points were uncorrected. 1H
NMR spectra were acquired at 500.1 MHz, and the chemical shifts were relative to internal TMS
( 0.00 ppm). Diastereomeric ratios were determined by integration of 1H NMR signals. 13C
NMR spectra were acquired at 125.8 MHz, and the chemical shifts were relative to the solvent
signal (CDCl3,  77.16 ppm). HRMS data were measured on a TOF mass spectrometer by
positive-ion ESI or, in one instance, by APCI.
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General procedure for the formation of allenyl aryl alcohols: 2-methyl-1-phenylbuta-2,3-
dien-1-ol (11a). Based on the method of Mukaiyama and Harada,15 1-bromo-2-butyne (1.59 g,
12.0 mmol) was added to a mixture of SnCl2 (2.53 g, 13.4 mmol) and NaI (2.04 g, 13.6 mmol) in
DMF (20 mL), and the solution was stirred at rt for 1 h. The solution was cooled to 0 °C, a
solution of benzaldehyde 10 (0.864 g, 8.14 mmol) in DMF (10 mL) was added, and the solution
was stirred overnight as the solution attained rt. Water was added, and the mixture was extracted
with diethyl ether (×3). The combined ether extracts were washed with water (×3) and brine,
dried over MgSO4, and concentrated by rotary evaporation. Flash chromatography (5 to 20%
diethyl ether in pentane) of the residue provided the allenyl aryl alcohol 11a (1.12 g, 86%) as an
oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.33 (4H, m), 7.29 (1H, t, J = 7.0 Hz), 5.11 (1H, m),
4.91 (2H, m), 2.16 (1H, broad s), 1.58 (3H, t, 5J = 3.8 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ
204.7, 141.8, 128.4 (2C), 127.8, 126.6 (2C), 102.7, 77.9, 74.7, 14.6; HRMS (ESI-TOF) m/z: [M
+ Na]+ Calcd for C11H12ONa 183.0780; Found 183.0782. NMR spectra are in accord with the
literature.30,31
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2-Methyl-1-(2-methylphenyl)buta-2,3-dien-1-ol (12a). 1-Bromo-2-butyne (1.62 g, 12.2 mmol),
SnCl2 (2.61 g, 13.8 mmol), NaI (1.95 g, 13.0 mmol), and 2-methylbenzaldehyde (1.24 g, 10.4
mmol) in DMF (30 mL) gave 12a (1.43 g, 79%) as an oil. 1H NMR (500 MHz, CDCl3) δ 7.44
(1H, d, J = 7.9 Hz), 7.22-7.14 (3H, m), 5.34 (1H, narrow m), 4.86-4.84 (2H, m), 2.34 (3H, s),
2.03 (1H, d, J = 3.6 Hz), 1.58 (3H, t, 5J = 2.7 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 205.4,
139.5, 135.8, 130.5, 127.5, 126.3, 126,0, 101.7, 77.2, 71.8, 19.2, 14.6; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C12H14ONa 197.0937; Found 197.0930.
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2-Methyl-1-(3-methylphenyl)buta-2,3-dien-1-ol (13a). 1-Bromo-2-butyne (0.805 g, 6.05
mmol), SnCl2 (1.32 g, 6.96 mmol), NaI (1.05 g, 7.00 mmol), and 3-methylbenzaldehyde (0.602
g, 5.00 mmol) in DMF (15 mL) gave 13a (526 mg, 60%) as a white foam. 1H NMR (500 MHz,
CDCl3) δ 7.24 (1H, t, J = 7.5 Hz), 7.19 (1H, s), 7.17 (1H, d, J = 7.7 Hz), 7.10 (1H, d, J = 7.4 Hz),
5.06 (1H, m), 4.92 (2H, m), 2.36 (3H, s), 2.14 (1H, d, J = 4.3 Hz), 1.58 (3H, t, 5J = 3.1 Hz);
13C{1H} NMR (126 MHz, CDCl3) δ 204.7, 141.7, 138.0, 128.5, 128.6, 127.2, 123.7, 102.7, 77.9,
74.7, 21.5, 14.6; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H14ONa 197.0937; Found
197.0937.
2-Methyl-1-(4-methylphenyl)buta-2,3-dien-1-ol (14a). 1-Bromo-2-butyne (1.57 g, 11.8 mmol),
SnCl2 (2.63 g, 13.9 mmol), NaI (1.98 g, 13.2 mmol), and 4-methylbenzaldehyde (1.24 g, 10.3
mmol) in DMF (30 mL) gave 14a (1.50 g, 84%) as an oil. 1H NMR (500 MHz, CDCl3) δ 7.26
(2H, d, J = 7.8 Hz), 7.15 (2H, d, J = 7.8 Hz), 5.06 (1H, m), 4.91-4.90 (2H, m), 2.34 (3H, s), 2.26
(1H, very broad), 1.57 (3H, t, 5J = 3.1 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 204.7, 138.9,
137.5, 129.1 (2C), 126.5 (2C), 102.8, 77.8, 74.5, 21.2, 14.7; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C12H14ONa 197.0937; Found 197.0940. NMR spectra are in accord with the
literature.31
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1-(3,5-Di-tert-butylphenyl)-2-methylbuta-2,3-dien-1-ol (15a). 1-Bromo-2-butyne (0.790 g,
5.93 mmol), SnCl2 (1.32 g, 6.96 mmol), NaI (1.05 g, 7.0 mmol), and 3,5-di-tert-
7
8
9
butylbenzaldehyde (0.502 g, 2.29 mmol) in DMF (15 mL) gave 15a (170 mg, 27%) as an oil. 1H
NMR (500 MHz, CDCl3) δ 7.34 (1H, t, J = 1.6 Hz), 7.20 (2H, broadened s), 5.09 (1H, m), 4.90
(2H, m), 2.12 (1H, d, J = 4.4 Hz), 1.61 (3H, t, 5J = 3.1 Hz), 1.32 (18H, s); 13C{1H} NMR (126
MHz, CDCl3) δ 204.9, 150.7 (2C), 140.9, 121.8, 120.8 (2C), 102.8, 77.6, 75.3, 34.9 (2C), 31.5
(6C), 14.9; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H28ONa 295.2023; Found 295.2023.
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2-Methyl-1-(3-(trifluoromethyl)phenyl)buta-2,3-dien-1-ol (16a). 1-Bromo-2-butyne (0.790 g,
5.93 mmol), SnCl2 (2.62 g, 13.8 mmol), NaI (2.06 g, 13.8 mmol), and 3-
(trifluoromethyl)benzaldehyde (1.73 g, 9.94 mmol) in DMF (30 mL) gave 16a (1.18 g, 52%) as
an oil. 1H NMR (500 MHz, CDCl3) δ 7.69 (1H, s), 7.60 (1H, d, J = 7.7 Hz), 7.59 (1H, d, J = 7.7
Hz), 7.51 (1H, t, J = 7.7 Hz), 5.23 (1H, m), 4.96 (2H, m), 2.26 (1H, d, J = 4.0 Hz), 1.62 (3H, t, 5J
= 3.1 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 205.0, 142.8, 130.8 (q, J ≈ 30 Hz), 129.9, 128.7,
124.6, 124.3 (q, J = 270 Hz), 123.4, 102.1, 78.1, 74.3, 14.3; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C12H11F3ONa 251.0654; Found 251.0649.
2-Methyl-1-(4-(trifluoromethyl)phenyl)buta-2,3-dien-1-ol (17a). 1-Bromo-2-butyne (1.49 g,
11.2 mmol), SnCl2 (2.62 g, 13.8 mmol), NaI (2.00 g, 13.4 mmol), and 4-
(trifluoromethyl)benzaldehyde (1.59 g, 9.12 mmol) in DMF (30 mL) gave 17a (1.05 g, 51%) as
an oil. 1H NMR (500 MHz, CDCl3) δ 7.64 (2H, d, J = 8.1 Hz), 7.54 (2H, d, J = 8.1 Hz), 5.24
(1H, m), 4.95 (2H, m), 2.28 (1H, broad), 1.62 (3H, t, 5J = 3.0 Hz); 13C{1H} NMR (126 MHz,
CDCl3) δ 205.0, 145.8, 129.9 (q, J = 32 Hz), 126.8 (2C), 125.2 (2C), 123.3 (q, J = 270 Hz),
102.1, 78.0, 74.3, 14.2; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H11F3ONa 251.0651;
Found 251.0649.
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2-Methyl-1-(4-(methylthio)phenyl)buta-2,3-dien-1-ol (18a). 1-Bromo-2-butyne (0.41 g, 3.1
mmol), SnCl2 (0.53 g, 2.8 mmol), NaI (0.42 g, 2.8 mmol), and 4-(methylthio)benzaldehyde
(0.304 g, 2.00 mmol) in DMF (10 mL) gave 18a (227 mg, 55%) as an oil. 1H NMR (500 MHz,
CDCl3) δ 7.30 (2H, d, J = 8.1 Hz), 7.24 (2H, d, J = 8.1 Hz), 5.07 (1H, m), 4.91 (2H, m), 2.48
(3H, s), 2.15 (1H, broad), 1.56 (3H, t, 5J = 2.7 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 204.7,
138.8, 137.9, 127.1 (2C), 126.6 (2C), 102.6, 77.9, 74.3, 15.9, 14.6; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C12H14OSNa 229.0658; Found 229.0662.
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2-Methyl-1-(3-methoxyphenyl)buta-2,3-dien-1-ol (19a). 1-Bromo-2-butyne (0.927 g, 6.97
mmol), SnCl2 (1.55 g, 8.18 mmol), NaI (1.23 g, 8.34 mmol), and 3-methoxybenzaldehyde (0.799
g, 5.88 mmol) in DMF (15 mL) gave 19a (0.609 g, 55%) as an oil. 1H NMR (500 MHz, CDCl3) δ
7.30 (1H, t, J = 8.0 Hz), 7.00-6.98 (2H, m), 6.87 (1H, dd, J = 6.0, 2.0 Hz), 5.12 (1H, s), 4.94 (2H,
m), 3.85 (3H, s), 2.21 (1H, d, J = 4.0 Hz), 1.62 (3H, t, 5J = 3.0 Hz); 13C{1H} NMR (126 MHz,
CDCl3) δ 204.8, 159.7, 143.5, 129.4, 119.0, 113.3, 112.1, 102.6, 77.8, 74.6, 55.3, 14.5; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C12H14O2Na 213.0886; Found 213.0894.
1-(Benzo[d][1,3]dioxol-5-yl)-2-methylbuta-2,3-dien-1-ol (20a). 1-Bromo-2-butyne (0.552 g,
4.15 mmol), SnCl2 (1.06 g, 5.59 mmol), NaI (0.84 g, 5.6 mmol), and piperonal (0.604 g, 4.02
mmol) in DMF (15 mL) gave 20a (0.498 g, 61%) as an oil. 1H NMR (500 MHz, CDCl3) δ 6.86
(1H, s), 6.82 (1H, d, J = 8.0 Hz), 6.75 (1H, d, J = 8.0 Hz), 5.92 (2H, s), 4.98 (1H, m), 4.89 (2H,
m), 2.39 (1H, broad s), 1.55 (3H, t, 5J = 3.0 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 204.4,
147.7, 147.2, 135.8, 120.2, 107.9, 107.0, 102.8, 101.0, 78.1, 74.3, 14.7; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C12H12O3Na 227.0679; Found 227.0672.
2-Methyl-1-(3,4,5-trimethoxyphenyl)buta-2,3-dien-1-ol (21a). 1-Bromo-2-butyne (0.552 g,
4.15 mmol), SnCl2 (1.32 g, 6.96 mmol), NaI (1.05 g, 7.00 mmol), and 3,4,5-
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trimethoxybenzaldehyde (0.981 g, 5.01 mmol) in DMF (15 mL) gave 21a (0.720 g, 57%) as an
oil. 1H NMR (500 MHz, CDCl3) δ 6.61 (2H, s), 5.05 (1H, s), 4.92 (2H, m), 3.87 (6H, s), 3.84
(3H, s), 2.23 (1H, broad s), 1.60 (t, 3H, 5J = 3.0 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 204.8,
153.2 (2C), 137.4 (2C), 103.7 (2C), 102.6, 77.9, 74.8, 60.8, 56.2 (2C), 14.6; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C14H18O4Na 273.1097; Found 273.1100.
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2-Methyl-1-(naphthalen-1-yl)buta-2,3-dien-1-ol (22a). 1-Bromo-2-butyne (0.365 g, 2.74
mmol), SnCl2 (0.568 g, 3.00 mmol), NaI (0.450 g, 3.02 mmol), and 1-naphthaldehyde (0.173 g,
1.10 mmol) in DMF (10 mL) gave 22a (193 mg, 83%) as an oil. 1H NMR (500 MHz, CDCl3) δ
8.18 (1H, d, J = 8.3 Hz), 7.86 (1H, d, J = 7.9 Hz), 7.79 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 7.1
Hz), 7.52-7.45 (3H, m, 3H), 5.88 (1H, m), 4.89 (2H, m), 2.27 (1H, broad), 1.60 (3H, t, 5J = 3.0
Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 205.7, 136.9, 133.9, 131.0, 128.7, 128.5, 126.0, 125.6,
125.2, 124.4, 123.9, 102.2, 77.5, 74.4, 14.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C15H14ONa 233.0937; Found 233.0938.
2-Methyl-1-(pyren-1-yl)buta-2,3-dien-1-ol (23a). 1-Bromo-2-butyne (0.349 g, 2.63 mmol),
SnCl2 (0.57 g, 3.0 mmol), NaI (0.45 g, 3.0 mmol), and pyrene-1-carbaldehyde (0.500 g, 2.17
mmol) in DMF (10 mL) gave 23a (517 mg, 84%) as an amorphous solid. 1H NMR (500 MHz,
CDCl3) δ 8.42 (1H, d, J = 9.3 Hz), 8.19 (4H, narrow m), 8.12 (1H, d, J = 9.3 Hz), 8.06 (2H,
apparent s), 8.02 (1H, t, J = 7.6 Hz), 6.19 (1H, m), 4.95 (2H, m), 2.45 (1H, broad), 1.63 (3H, t, 5J
= 3.1 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 205.4, 134.8, 131.3, 131.0, 130.7, 128.5, 127.6,
127.5, 127.4, 126.0, 125.3, 125.2, 125.0, 124.85, 124.79, 124.5, 123.1, 102.9, 77.9, 72.2, 14.9;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H16ONa 307.1093; Found 307.1107.
2-Methyl-1-(naphthalen-2-yl)buta-2,3-dien-1-ol (24a). 1-Bromo-2-butyne (1.58 g, 11.9
mmol), SnCl2 (2.47 g, 13.0 mmol), NaI (1.95 g, 13.0 mmol), and 2-naphthaldehyde (1.48 g, 9.48
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mmol) in DMF (30 mL) gave 24a (1.34 g, 67%) as an oil. 1H NMR (500 MHz, CDCl3) δ 7.85-
7.81 (4H, m), 7.50-7.45 (3H, m), 5.28 (1H, m), 4.95 (2H, m), 2.30 (1H, d, J = 3.6 Hz), 1.59 (3H,
t, 5J = 3.1 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 204.9, 139.2, 133.2, 133.1, 128.2, 128.0,
127.7, 126.1, 125.9, 125.5, 124.5, 102.6, 77.9, 74.8, 14.6; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C15H14ONa 233.0937; Found 233.0927.
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1-Mesityl-2-methylbuta-2,3-dien-1-ol (25a). 1-Bromo-2-butyne (1.43 g, 10.7 mmol), SnCl2
(2.54 g, 13.4 mmol), NaI (1.93 g, 13.4 mmol), and mesitaldehyde (1.36 g, 9.24 mmol) in DMF
(30 mL) gave 25a (1.25 g, 68 %) as an oil. 1H NMR (500 MHz, CDCl3) δ 6.81 (2H, s), 5.56 (1H,
m), 4.90 (2H, narrow m), 2.37 (6H, s), 2.27 (1H, broad), 2.24 (3H, s), 1.55 (3H, t, 5J = 2.9 Hz);
13C{1H} NMR (126 MHz, CDCl3) δ 203.8, 137.3 (2C), 137.0, 133.4, 130.0 (2C), 102.5, 78.8,
69.5, 20.8, 20.4 (2C), 15.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H18ONa 225.1250;
Found 225.1249. NMR spectra are in accord with the literature.32
General procedure for the oxidation of allenyl aryl alcohols: 2-methyl-1-phenylbuta-2,3-
dien-1-one (11b). Based on the method of Frigerio et al.,17 a solution of IBX (0.84 g, 3.0 mmol)
and allenyl aryl alcohol 11a (344 mg, 2.15 mmol) in DMSO (9.0 mL) was stirred at rt for 1 h.
Water was added to precipitate IBX by-products, which were removed by filtration through a
sintered glass funnel. The filtrate was extracted with ethyl acetate (×3), and the combined
organic layers were washed with water (×3) and then brine. The solution was dried over Na2SO4
and concentrated by rotary evaporation to yield the ketone 11b (227 mg, 67%) as an oil. 1H
NMR (500 MHz, CDCl3) δ 7.75 (2H, dd, J = 7.7, 0.5 Hz), 7.49 (1H, tt, J = 7.6, 0.5 Hz), 7.38
(2H, t, J = 7.6 Hz), 5.01 (2H, q, 5J = 2.9 Hz), 2.01 (3H, t, 5J = 2.9 Hz); 13C{1H} NMR (126 MHz,
CDCl3) δ 217.5, 195.0, 138.2, 131.9, 129.0 (2C), 127.8 (2C), 102.1, 78.3, 14.7; HRMS (ESI-
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2-Methyl-1-(2-methylphenyl)buta-2,3-dien-1-one (12b). Alcohol 12a (210 mg, 1.21 mmol)
and IBX (470 mg, 1.68 mmol) in DMSO (2.5 mL) gave 12b (76 mg, 37%) as an oil. 1H NMR
(500 MHz, CDCl3) δ 7.29-7.27 (2H, m), 7.19-7.13 (2H, m), 4.87 (2H, q, 5J = 3.0 Hz), 2.32 (3H,
s), 1.98 (3H, t, 5J = 3.0 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 218.4, 198.4, 139.4, 135.7,
130.5, 129.7, 127.7, 124.6, 104.3, 78.1, 19.6, 13.6; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C12H12ONa 195.0780; Found 195.0786.
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2-Methyl-1-(3-methylphenyl)buta-2,3-dien-1-one (13b). Alcohol 13a (520 mg, 2.99 mmol)
and IBX (1.17 g, 4.18 mmol) in DMSO (5.0 mL) gave 13b (308 mg, 60%) as an oil. 1H NMR
(500 MHz, CDCl3) δ 7.55 (2H, narrow m), 7.32-7.24 (2H, m), 5.00 (2H, q, 5J = 3.0 Hz), 2.38
(3H, s), 2.00 (3H, t, 5J = 3.0 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 217.5, 195.3, 138.2, 137.7,
132.7, 129.5, 127.6, 126.3, 102.1, 78.2, 21.4, 14.8; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C12H12ONa 195.0780; Found 195.0784.
2-Methyl-1-(4-methylphenyl)buta-2,3-dien-1-one (14b). Alcohol 14a (511 mg, 2.94 mmol)
and IBX (1.12 g, 3.99 mmol) in DMSO (15 mL) gave 14b (229 mg, 45%) as an oil. 1H NMR
(500 MHz, CDCl3) δ 7.69 (2H, d, J = 7.6 Hz), 7.19 (2H, d, J = 7.6 Hz), 5.00 (2H, q, 5J = 2.7 Hz),
2.39 (3H, s), 2.00 (3H, t, 5J = 2.7 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 217.1, 194.6, 142.6,
135.5, 129.2 (2C), 128.5 (2C), 101.9, 78.2, 21.6, 14.9; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C12H12ONa 195.0780; Found 195.0780. NMR spectra are in accord with the literature.34
1-(3,5-Di-tert-butylphenyl)-2-methylbuta-2,3-dien-1-one (15b). Alcohol 15a (169 mg, 0.62
mmol) and IBX (0.24 g, 0.86 mmol) in DMSO (2 mL) gave 15b (53 mg, 32%) as an oil. 1H
NMR (500 MHz, CDCl3) δ 7.62 (2H, d, J = 1.8 Hz), 7.55 (1H, t, J = 1.8 Hz), 4.99 (2H, q, 5J =
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2.9 Hz), 2.00 (3H, t, 5J = 2.9 Hz), 1.32 (18H, s); 13C{1H} NMR (126 MHz, CDCl3) δ 217.3,
195.6, 150.3 (2C), 137.5, 126.1, 123.6 (2C), 102.0, 77.8, 34.9 (2C), 31.4 (6C), 15.0; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C19H26ONa 293.1876; Found 293.1872.
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2-Methyl-1-(3-(trifluoromethyl)phenyl)buta-2,3-dien-1-one (16b). Alcohol 16a (200 mg,
0.876 mmol) and IBX (0.34 g, 1.2 mmol) in DMSO (3 mL) gave 16b (106 mg, 54%) as an oil.
1H NMR (500 MHz, CDCl3) δ 8.05 (1H, s), 7.96 (1H, d, J = 7.8 Hz), 7.78 (1H, d, J = 7.8 Hz),
7.57 (1H, t, J = 7.8 Hz), 5.10 (2H, q, 5J = 2.9 Hz), 2.06 (3H, t, 5J = 2.9 Hz); 13C{1H} NMR (126
MHz, CDCl3) δ 218.0, 193.6, 138.6, 132.1, 130.3 (q, J = 33 Hz), 128.5, 128.3 (q, J = 4 Hz),
126.1 (q, J = 4 Hz), 102.2, 79.0, 14.5, CF3 signal not discerned; HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C12H9F3ONa 249.0498; Found 249.0487.
2-Methyl-1-(4-(trifluoromethyl)phenyl)buta-2,3-dien-1-one (17b). Alcohol 17a (526 mg, 2.31
mmol) and IBX (0.911 g, 3.25 mmol) in DMSO (15 mL) gave 17b (433 mg, 83%) as an oil. 1H
NMR (500 MHz, CDCl3) δ 7.86 (2H, d, J = 8.0 Hz), 7.69 (2H, d, J = 8.0 Hz), 5.10 (2H, q, 5J =
3.1 Hz), 2.05 (3H, t, 5J = 3.1 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 218.0, 194.1, 141.2, 133.2
(q, J = 33 Hz), 129.2 (2C), 124.9 (2C, q, J = 4 Hz), 102.4, 79.0, 14.4 (CF3 signal not discerned);
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H10F3O 227.0678; Found 227.0673.
2-Methyl-1-(4-(methylthio)phenyl)buta-2,3-dien-1-one (18b). Alcohol 18a (220 mg, 1.07
mmol) and IBX (0.411 g, 1.46 mmol) in DMSO (5.0 mL) gave 18b (159 mg, 73%) as an oil. 1H
NMR (500 MHz, CDCl3) δ 7.72 (2H, d, J = 7.9 Hz), 7.22 (2H, d, J = 7.9 Hz), 5.02 (2H, q, 5J =
2.4 Hz), 2.51 (3H, s), 2.00 (3H, t, 5J = 2.4 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 216.9, 193.8,
144.4, 134.3, 129.6 (2C), 124.5 (2C), 101.8, 78.2, 14.9 (2C); HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C12H12OSNa 227.0501; Found 227.0492.
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2-Methyl-1-(3-methoxyphenyl)buta-2,3-dien-1-one (19b). Alcohol 19a (250 mg, 1.31 mmol)
and IBX (0.508 g, 1.81 mmol) in DMSO (5.0 mL) gave 19b (169 mg, 69%) as an oil. 1H NMR
(500 MHz, CDCl3) δ 7.38 (1H, d, J = 7.6 Hz), 7.34-7.29 (2H, m), 7.07 (1H, dd, J = 8.2, 2.5 Hz),
5.05 (2H, q, 5J = 2.5 Hz), 3.85 (3H, s), 2.03 (3H, t, 5J = 2.5 Hz); 13C{1H} NMR (126 MHz,
CDCl3) δ 217.4, 194.7, 159.2, 139.4, 128.8, 121.7, 118.2, 113.7, 102.0, 78.4, 55.4, 14.8; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C12H12O2Na 211.0730; Found 211.0728.
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1-(Benzo[d][1,3]dioxol-5-yl)-2-methylbuta-2,3-dien-1-one (20b). Alcohol 20a (1.89 g, 9.19
mmol) and IBX (3.62 g, 12.9 mmol) in DMSO (15 mL) gave 20b (1.70 g, 91%) as an oil. 1H
NMR (500 MHz, CDCl3) δ 7.43 (1H, dd, J = 8.1, 1.6 Hz), 7.29 (1H, d, J = 1.6 Hz), 6.79 (1H, d,
J = 8.1 Hz), 6.01 (2H, s), 5.02 (2H, q, 5J = 3.0 Hz), 1.99 (3H, t, 5J = 3.0 Hz); 13C{1H} NMR (126
MHz, CDCl3) δ 216.4, 192.9, 151.0, 147.5, 132.3, 125.2, 109.3 (2C), 107.4, 101.7, 78.1, 15.1;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H10O3Na 225.0522; Found 225.0524.
2-Methyl-1-(3,4,5-trimethoxyphenyl)buta-2,3-dien-1-one (21b). Alcohol 21a (698 mg, 2.79
mmol) and IBX (1.09 g, 3.89 mmol) in DMSO (10 mL) gave 21b (489 mg, 71%) as a yellow
solid. mp 70-73 °C; 1H NMR (500 MHz, CDCl3) δ 7.11 (2H, s), 5.06 (2H, q, 5J = 2.8 Hz), 3.92
(3H, s), 3.90 (6H, s), 2.03 (3H, t, 5J = 2.8 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 216.7, 193.5,
152.5 (2C), 141.8, 133.0, 106.9, 101.7 (2C), 78.1, 60.9, 56.2 (2C), 15.2; HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C14H16O4Na 271.0941; Found 271.0942.
2-Methyl-1-(naphthalen-1-yl)buta-2,3-dien-1-one (22b). Alcohol 22a (823 mg, 3.92 mmol)
and IBX (2.65 g, 9.46 mmol) in DMSO (15 mL) gave 22b (706 mg, 87%) as an oil. 1H NMR
(500 MHz, CDCl3) δ 8.05 (1H, d, J = 8.2 Hz), 7.90 (1H, d, J = 8.2 Hz), 7.85 (1H, d, J = 7.8 Hz),
7.56 (1H, d, J = 7.1 Hz), 7.53-7.46 (2H, m), 7.42 (1H, t, J = 7.6 Hz), 4.79 (2H, broad s), 2.09
(3H, broad s); 13C{1H} NMR (126 MHz, CDCl3) δ 218.6, 197.6, 136.9, 133.5, 130.7, 130.5,
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128.3, 127.0, 126.6, 126.1, 125.4, 124.0, 104.9, 78.3, 13.9; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C15H12ONa 231.0780; Found 231.0784. NMR spectra are in accord with the
literature.35
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2-Methyl-1-(pyren-1-yl)buta-2,3-dien-1-one (23b). Alcohol 23a (260 mg, 0.915 mmol) and
IBX (0.351 g, 1.25 mmol) in DMSO (2.5 mL) gave 23b (172 mg, 67%) as an oil. 1H NMR (500
MHz, CDCl3) δ 8.37 (1H, d, J = 9.2 Hz), 8.26 (2H, d, J = 7.6 Hz), 8.18-8.09 (5H m), 8.07 (1H, t,
J = 7.6 Hz), 4.79 (2H, q, 5J = 2.9 Hz), 2.22 (3H, t, 5J = 2.9 Hz); 13C{1H} NMR (126 MHz,
CDCl3) δ 218.9, 198.0, 134.2, 132.6, 131.2, 130.7, 129.0, 128.7, 128.5, 127.2, 126.2, 126.0,
125.8, 125.7, 124.8, 124.6, 124.5, 123.4, 105.4, 78.4, 14.0; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C21H14ONa 305.0937; Found 305.0939
2-Methyl-1-(naphthalen-2-yl)buta-2,3-dien-1-one (24b). Alcohol 24a (1.35 g, 8.63 mmol) and
IBX (3.40 g, 12.1 mmol) in DMSO (10 mL) gave 24b (1.05 g, 79%) as a solid. mp 39.5-42 °C;
1H NMR (500 MHz, CDCl3) δ 8.31 (1H, s), 7.92 (1H, d, J = 8.0 Hz), 7.88-7.84 (3H, m), 7.59-
7.51 (2H, m), 5.04 (2H, q, 5J = 2.9 Hz), 2.08 (3H, t, 5J = 2.9 Hz); 13C{1H} NMR (126 MHz,
CDCl3) δ 217.5, 194.9, 135.4, 135.1, 132.2, 130.3, 129.3, 127.9, 127.77, 127.67, 126.5, 125.3,
102.3, 78.4, 14.9; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H12ONa 231.0780; Found
231.0784.
1-Mesityl-2-methylbuta-2,3-dien-1-one (25b). Alcohol 25a (620 mg, 3.07 mmol) and
IBX (1.21 g, 4.32 mmol) in DMSO (15 mL) gave 25b (457 mg, 74%) as an oil. 1H NMR (500
MHz, CDCl3) δ 6.77 (2H, s), 4.82 (2H, narrow m), 2.26 (3H, s), 2.14 (6H, s), 1.96 (3H, t, 5J =
2.8 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ 218.0, 201.4, 138.2, 137.9 (2C), 133.6, 127.8 (2C),
105.1, 77.5, 21.1, 19.0 (2C), 12.8; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H16ONa
223.1093; Found 223.1093.
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General procedure for the BF3 etherate cyclization of AAKs. A 0.06 to 0.1 M solution of the
AAK in CH2Cl2 was stirred with BF3 etherate (1.5 equiv) at temperatures between -78 °C and rt,
and the course of the reaction was monitored by tlc. To stop the reaction, saturated aqueous
NaHCO3 was added, and the aqueous layer was extracted with CH2Cl2 (×3). The combined
organic layers were dried over Na2SO4 and concentrated by rotary evaporation. Flash
chromatography (5-20% ether in pentane) or the residue provided the product. Exact reaction
temperatures, times, yields and product ratios are given in Scheme 4.
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General procedure for the In(OTf)3 cyclization of AAKs. A 0.05 to 0.08 M solution of the
AAK in CH2Cl2 was stirred with In(OTf)3 at rt, except for 19b which was at 0 °C, and the course
of the reaction was followed by tlc. To stop the reaction, saturated aqueous NaHCO3 was added,
and the aqueous layer was extracted with CH2Cl2 (×3). The combined organic layers were dried
over Na2SO4 and concentrated by rotary evaporation. Flash chromatography (5-20% ether in
pentane) or the residue provided the product. The molar equivalents of In(OTf)3, reaction
temperatures, times and yields are given in Scheme 4.
2-Methyl-3-methylene-2,3-dihydro-1H-inden-1-one (11c) and 2,3-dimethyl-1H-inden-1-one
(11d). With BF3 etherate: 11b (144.5 mg) gave an inseparable mixture of 11c and 11d in a ratio
of 7:1, respectively (74.4 mg, 51%) as an oil. For 11c: 1H NMR (500 MHz, CDCl3) δ 7.79 (2H,
broadened d, J = 8.2 Hz), 7.65 (1H, t, J = 7.5 Hz), 7.44 (1H, t, J = 7.5 Hz), 5.84 (1H, s), 5.31
(1H, s), 3.14 (1H, q, J = 7.5 Hz), 1.39 (3H, d, J = 7.5 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ
206.1, 148.8, 146.3, 135.7, 135.0, 129.4, 123.7, 121.2, 107.0, 46.0, 14.6. For 11d: 1H NMR (500
MHz, CDCl3) δ 7.36 (1H, d, J = 7.1 Hz), 7.31 (1H, t, J = 7.4 Hz), 7.15 (1H, t, J = 7.4 Hz), 7.00
(1H, d, J = 7.0 Hz), 2.11 (3H, s), 1.81 (3H, s). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
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