Concise synthesis of functionalized benzocyclobutenones

Article abstract of DOI:10.1016/j.tet.2014.03.080

A concise approach to access functionalized benzocyclobutenones from 3-halophenol derivatives is described. This modified synthesis employs a [2+2] cycloaddition between benzynes generated from dehydrohalogenation of aryl halides using LiTMP and acetaldehyde enolate generated from n-BuLi and THF, followed by oxidation of the benzocyclobutenol intermediates to provide benzocyclobutenones. The [2+2] reaction can be run on a 10-g scale with an increased yield. A number of functional groups including alkenes and alkynes are tolerated. Coupling of benzynes with ketene silyl acetals to give 8-substituted benzocyclobutenones is also demonstrated.

Full text of DOI:10.1016/j.tet.2014.03.080

Tetrahedron 70 (2014) 4135e4146
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Concise synthesis of functionalized benzocyclobutenones
y
y
*
P.-H. Chen , Nikolas A. Savage , Guangbin Dong
Department of Chemistry, University of Texas at Austin, Austin, TX 78712, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise approach to access functionalized benzocyclobutenones from 3-halophenol derivatives is de-
scribed. This modified synthesis employs a [2þ2] cycloaddition between benzynes generated from de-
hydrohalogenation of aryl halides using LiTMP and acetaldehyde enolate generated from n-BuLi and THF,
followed by oxidation of the benzocyclobutenol intermediates to provide benzocyclobutenones. The
[2þ2] reaction can be run on a 10-g scale with an increased yield. A number of functional groups in-
cluding alkenes and alkynes are tolerated. Coupling of benzynes with ketene silyl acetals to give 8-
substituted benzocyclobutenones is also demonstrated.
Received 26 January 2014
Received in revised form 21 March 2014
Accepted 24 March 2014
Available online 3 April 2014
Keywords:
Benzocyclobutenone
Cycloaddition
Ó 2014 Elsevier Ltd. All rights reserved.
Benzyne
Dehydrohalogenation
Benzocyclobutenol
1. Introduction
generally prepared in one step from the corresponding ester.9 The
substrates (1 and 2) employed in our methodologies are generally
Benzocyclobutenones are a unique class of compounds with rich
reactivity, thus often serve as value building blocks for organic
synthesis.1 Ring-opening of benzocyclobutenones is known to be
triggered by heat2 or nucleophiles,3 and also known to be facilitated
by transition metals.4 Combining further reactions of metal-carbon
bonds, transition metal-mediated CeC bond cleavage of benzocy-
clobutenones can lead to new transformations for preparing novel
structures.5 For example, recently we have developed intra-
molecular couplings between benzocyclobutenones and olefins to
give fused rings and spirocycles, respectively (Fig. 1).6 A divergent
prepared with an additional step from 3 via direct alkylation or
Mitsunobu reaction, thus requiring 7e8 steps total, which signifi-
cantly diminished the practicality of these methodologies. Hence,
to address the abovementioned challenge, a more efficient and
practical synthesis of functionalized benzocyclobutenones is
needed. In this article, we describe our development of a concise
approach to access the substituted benzocyclobutenones, including
those with alkene and alkyne moieties.
The synthesis of benzocyclobutenones is non-trial and has been
an ongoing research. While a number of innovative approaches are
available,10 [2þ2] cycloaddition between an aryne and a ketene
equivalent still represents the most popular way to prepare ben-
zocyclobutenones.11 In 1982, Bisacchi and Stevens developed the
first [2þ2] cycloaddition to prepare benzocyclobutenones, in which
the benzyne was generated from dehydrobromination of aryl bro-
mides with sodium amide, and 1,1-dimethoxyethylene was used as
the ketene equivalent.12 While this method is widely useful, heat-
ing (75e80 ꢀC) is generally required and preparation of 1,1-
dimethoxyethylene is not convenient.13 Consequently, Santelli,
Ibrahim-Ouali and co-workers later found 1,1-dimethoxyethylene
can be substituted with commercially available 2-methylene-1,3-
dioxepane as the [2þ2] partner albeit giving lower yields.14 Due
to the harsh conditions to generate benzynes from sodium amide,
Suzuki and co-workers developed a mild procedure to synthesize
benzocyclobutenones through generating the corresponding
arynes via halogen-metal exchange followed by elimination of an
ortho-triflate (vide supra, Fig. 2).8 Another advantage of Suzuki’s
method is using ketene silyl acetals as the coupling partner because
approach has also been developed to access fused b-naphthols and
indenes via direct and decarbonylative insertions of alkynes into
benzocyclobutenones.7 Structural motifs generated from these
methodologies have been found in a number of natural products.
While these methods are potentially useful and attractive for
synthesizing bioactive molecules, one key challenge is that the
benzocyclobutenone substrates containing alkene or alkyne func-
tional groups usually required more than six steps to prepare
(Fig. 2). For example, we previously employed a slightly modified
procedure first developed by Suzuki to access the key intermediate,
3-hydroxybenzocyclobutenone (3).8 Although reliable and scalable,
this synthetic route takes about six steps from resorcinol. In addi-
tion, while reagent 5 is commercially available, it is expensive and
* Corresponding author. Tel./fax: þ1 512 232 8220; e-mail address: gbdong@cm.
utexas.edu (G. Dong).
y
P.-H. Chen and N.A.S. contributed equally.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.080

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P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
Fig. 1. Rh-catalyzed coupling reactions between benzocyclobutenones and alkenes/alkynes.
Fig. 2. Synthesis of benzocyclobutenone substrates with alkene and alkyne moieties.
they are more readily available and easier to handle than 1,1-
dialkoxyethylene. Nevertheless, both ortho-iodo triflates and ke-
tene silyl acetals require additional steps to prepare. Therefore,
more efficient synthesis of benzocyclobutenones is still highly
sought after.
Our research was inspired by an anthracene synthesis first de-
veloped by Fleming in 1975, which involved a benzocyclobuten-
oxide intermediate from a [2þ2] addition between benzynes
[prepared from dehydrobromination of aryl bromides with
LiTMP (N-lithio-2,2,6,6-tetramethylpiperidine)], and acetaldehyde
enolates (in situ generated from THF with n-BuLi).15 Olofson and
co-workers later found the benzocyclobutenoxide intermediates
could be trapped by various electrophiles providing synthetically
useful structural motifs.16 In contrast, utilizing this [2þ2] reaction
to prepare benzocyclobutenols has been much less developed likely
due to the sensitivity of the benzocyclobutenoxide intermediates
that can undergo reversible ring opening to give the corresponding
highly reactive o-quinodimethanes. The work by Durst17 and more
recently by Kraus18 demonstrated the feasibility to capture the
benzocyclobutenol products using Fleming’s approach, although
few functional groups except methoxy groups have been examined
for compatibility. We were stimulated by the simplicity of this

P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
4137
approach to prepare benzocyclobutenols from relatively in-
expensive feedstock, i.e., aryl halides and THF, and expect sub-
Given that the CeC activation methodologies that we previously
developed6,7 require benzocyclobutenones containing olefin or
acetylene moiety, we next investigated the compatibility of CeC
double and triple bonds under the benzyne/enolate [2þ2] condi-
tions. A number of alkene or alkyne-substituted 3-halophenyl
ethers (6le6q) were prepared in good to excellent yields through
either direct alkylation (SN2) or Mitsunobu reaction23 (Table 3). To
our delight, these substrates all produced benzyne and underwent
[2þ2] cycloaddition smoothly; subsequent oxidation provided the
alkene/alkyne-tethered benzocyclobutenones in good overall
yields.24 This approach allows us to prepare the CeC activation
substrates in only three steps from inexpensive 3-halophenols.
Besides acetaldehyde lithium enolate generated from THF, ke-
tene silyl acetals were also found to be suitable coupling partners to
give protected benzocyclobutenones, which can be efficiently
deprotected using aqueous HF to reveal the ketones (Scheme 2).25
One advantage of this approach is that it allows for preparation of
8-substituted benzocyclobutenones rapidly from bromoarenes. Our
preliminary results indicated that 8-methyl and ethyl-substituted
benzocyclobutenones can be prepared in moderate to good yields
using this approach.
sequent oxidation19 would provide
a rapid way to access
benzocyclobutenones. Hence, our study began with optimizing the
reaction conditions for the synthesis of benzocyclobutenol, then
investigating the influence of functional groups including alkenes
and alkynes, and finally employing this approach to prepare func-
tionalized benzocyclobutenones via subsequent alcohol oxidation.
2. Result and discussions
Initial study employed 3-bromonanisole (6a) as the model
substrate (Table 1). LiTMP was used as the base to generate the
corresponding benzyne,20 and acetaldehyde enolate was produced
in situ from n-BuLi and THF. While previous studies took acetal-
dehyde enolate as the limiting reagent,17,18 we found higher yield of
Table 1
Selected optimization studies
3. Conclusion
In summary, we have modified a previously reported method to
synthesize benzocyclobutenone derivatives from 3-haloanisole and
acetaldehyde enolate and thus developed a simpler approach to
access substituted benzocyclobutenones from 3-halophenol de-
rivatives. This reaction sequence proves to be scalable and tolerates
a number of functional groups. Moreover, this approach stream-
lined the synthesis of our key CeC activation intermediate/sub-
strates 1e3 by halving the number of steps from the previous route;
thus, it makes the benzocyclobutenone/alkene and alkyne coupling
methodologies more attractive. Given the ease to generate acetal-
dehyde enolate and the ready availability of aryl halides, we expect
that this strategy will also be useful for preparing various other
benzocyclobutenols and benzocyclobutenones.
Entry
x
y
z
T
Yield (%)a
1
2
3
2
1
1
1
2
1.5
2.5
2.5
1.2
ꢁ40 ꢀC
ꢁ78 ꢀC
ꢁ78 ꢀC
62
70
71
a
Isolated yields: yields are based on the limiting reagent.
benzocyclobutenol 7a was obtained when aryl bromide 6a was
used as the limiting reagent (entry 2). In addition, cleaner reaction
was observed when it was set up at ꢁ78 ꢀC. Furthermore, we dis-
covered that large excess of acetaldehyde enolate and LiTMP were
not needed; use of 1.2 equiv of LiTMP and 1.5 equiv of n-BuLi pro-
vided benzocyclobutenol 7a in 71% isolated yield (the highest yield
reported previously is 50%18) (entry 3).
4. Experimental
4.1. General
With the optimized conditions in hand, we next examined the
aryl halide substrates with different substituents. A number of 3-
halo-substitued arenes were found to be suitable substrates pro-
viding the desired benzocyclobutenols (Table 2). Subsequent oxi-
dation with DesseMartin periodinane (DMP)21 afforded various
functionalized benzocyclobutenones in high yields. In general, both
aryl bromides and chlorides can be used as the benzyne precursor,
and the bromide substrate showed higher reactivity than the cor-
responding chlorides. In addition, 3,4 and 3,6-disubstituted ben-
zocyclobutenones can be obtained in high yields (entries 3, 4, 6). It
is interesting to note that substrate 6h containing two chlorides
worked well giving chloro-substituted benzocyclobutenone (8h).
While giving low yields, the OTBS-ether and dimethylaniline sub-
strates (6g, 6i, and 6j) showed feasibility for the [2þ2] cyclization.
Under our conditions, 2-bromoanisole exhibited very low reactivity
(entry 8). We were delighted to find that benzyl ethers were tol-
erated (6c and 6d). Given that benzyl protecting group is more
convenient to remove than a methyl group, we expect compound
6d would be a more suitable substrate for the synthesis of key in-
termediate 3. Indeed, the [2þ2] cycloaddition with commercially
available 6d gave benzocyclobutenol 7c on a 30-g scale, and the
crude product can be used for next step without purification.
Subsequent MoffatteSwern oxidation22 followed by benzyl-
deprotection with Pd(OH)2 and H2 provided 3-hydroxybenzo
cyclobutenone 3 in 75% overall yield on a 10-g scale over three
steps (Scheme 1).
THF was purchased from Fischer scientific, dried by filtration
through a Pure-Solv MD-5 Solvent Purification System (Innovative
Technology) and was distilled freshly over sodium. DCM was dried
by filtration through a Pure-Solv MD-5 Solvent Purification System
(Innovative Technology). All reagents were reagent grade and were
purchased and used without further purification. Analytical thin-
layer chromatography (TLC) was carried out using 0.2 mm com-
mercial silica gel plates (silica gel 60, F254, EMD chemical). High-
resolution mass spectra (HRMS) were obtained on a Karatos MS9
and are reported as m/z (relative intensity). Accurate masses are
reported for the molecular ion [MþNa]þ, [MþH]þ, [MꢁH]ꢁ or [M].
Infrared spectra were recorded on a Nicolet 380 FTIR using neat
thin film technique. Nuclear magnetic resonance spectra (1H NMR
and 13C NMR) were recorded with a Varian Gemini (400 MHz, 1H at
400 MHz, 13C at 100 MHz). Unless otherwise noted, all spectra were
acquired in CDCl3. Chemical shifts are reported in parts per million
(ppm,
d), downfield from tetramethylsilane (TMS,
d
¼0.00 ppm) and
are referenced to residual solvent (CDCl3,
d
¼7.26 ppm (1H) and
77.16 ppm (13C)). Coupling constants were reported in Hertz (Hz).
Data for 1H NMR spectra were reported as follows: chemical shift
(ppm, referenced to protium; s¼singlet, d¼doublet, t¼triplet,
q¼quartet, quin¼quintet, dd¼doublet of doublets, td¼triplet of
doublets, ddd¼doublet of doublet of doublets, m¼multiplet, cou-
pling constant (Hz), and integration). Compounds 6a, 6b, 6d, 6e, 6f,

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P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
Table 2
A two-step benzocyclobutenone synthesis: substrates with different substituents
Entry
1
Substrate
[2þ2] Producta
Oxidation productb
2
3
4
5
6
7
8
aOtherwise noted, general procedure C was applied.
bOtherwise noted, general procedure F was applied.
cGeneral procedure D was applied.
dGeneral procedure G was applied.
Scheme 1. Synthesis of 3-hydroxybenzocyclobentenone 3.
6i, 6j, and 6k are commercially available and used as purchased
without purification. 6c,26 6h,27 6r,28 and 6v29 are known com-
pounds from literature.
1.1 equiv), and THF (20 mL). With stirring, DIAD (6.6 mmol,
1.1 equiv) was added dropwise. Upon completion, the reaction was
heated to 60 ꢀC overnight. The reaction mixture was then con-
centrated under vacuum and directly purified via flash chroma-
tography on silica gel to afford the following compounds.
4.2. General procedure A: Mitsunobu reaction
To a 50 mL flamed-dried flask equipped with a stir bar and
a rubber septum were added phenol derivatives (6 mmol, 1 equiv),
PPh3 (6.6 mmol, 1.1 equiv), corresponding alcohols (6.6 mmol,
4.2.1. tert-Butyl(2-(3-chlorophenoxy)ethoxy)dimethylsilane
(6g). Compound 6g was obtained in 95% yield as a colorless oil
(652 mg) from 3-chlorophenol and 2-((tert-butyldimethylsilyl)-

P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
4139
Table 3
Substrates with alkene and alkyne functional groups
Entry
1
Substrate
[2þ2] Producta
Oxidation productb
2
3
4
5
6
7
8
9
10
11
12
aGeneral procedure C was applied.
bGeneral procedure F was applied.
cGeneral procedure B was applied.
dGeneral procedure A was applied.

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P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
131.6 (s), 130.2 (s), 128.2 (s), 127.7 (s), 123.6 (s), 120.8 (s), 114.9 (s),
113.1 (s), 88.8 (s), 81.3 (s), 66.6 (s), 28.3 (s), 16.1 (s). IR: n 2964, 2919,
1647, 1605, 1583, 1480, 1469, 1274, 1140, 1054, 893, 782 cmꢁ1. HRMS
calcd for C17H15ClO [M]: 270.0811, found: 270.0809.
4.2.6. (E)-1-Chloro-3-((2-phenylbut-2-en-1-yl)oxy)benzene
(6s). Compound 6s was obtained in 93% yield as a colorless oil
(957.9 mg) from 3-chlorophenol and (E)-2-phenylbut-2-en-1-ol,30
Rf¼0.8 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
d
7.40e7.33 (m, 2H), 7.31e7.22 (m, 3H), 7.16 (td, J¼8.4, 0.6 Hz, 1H),
6.92e6.88 (m, 2H), 6.78 (ddt, J¼8.3, 2.2, 1.0 Hz, 1H), 6.00e5.91 (m,
1H), 4.65 (dd, J¼2.2, 1.0 Hz, 2H), 1.67 (dt, J¼7.0, 1.2 Hz, 3H). 13C NMR
(101 MHz, CDCl3)
d 159.7 (s), 138.2 (s), 136.6 (s), 134.9 (s), 130.3 (s),
128.9 (s),128.5 (s),127.4 (s),126.4 (s),121.1 (s),115.5 (s),113.5 (s), 73.1
(s),14.8 (s). IR: 3055.89, 3022.11, 2984.13, 2915.73, 2858.38,1594.55,
1479.73, 1375.20, 1306.56, 1282.56, 1243.84, 1225.69, 1090.91,
1071.71, 1008.11, 893.99, 861.23, 838.07, 764.71, 701.87, 680.44 cmꢁ1
Scheme 2. Synthesis of 8-substituted benzocyclobutenones through coupling with
ketene silyl acetals.
n
.
oxy)ethan-1-ol, Rf¼0.7 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
HRMS calcd for C16H14ClO [M]: 257.0733, found: 257.0738.
CDCl3)
d
7.18 (t, J¼8.2 Hz,1H), 6.94e6.90 (m, 2H), 6.82e6.77 (m,1H),
4.02 (t, J¼4.9 Hz, 2H), 3.96 (t, J¼4.9 Hz, 2H), 0.91 (s, 9H), 0.10 (s, 6H).
4.2.7. (E)-1-Bromo-3-(hex-3-en-1-yloxy)benzene (6t). Compound
6t was obtained in 94% yield as a colorless oil (1.1948 g) from 3-
bromophenol and (E)-hex-3-en-1-ol, Rf¼0.8 (Hexane/EtOAc¼5:1);
13C NMR (101 MHz, CDCl3)
d
159.7 (s), 134.8 (s), 130.1 (s), 120.8 (s),
114.9 (s), 113.1 (s), 69.5 (s), 61.9 (s), 25.9 (s), 18.4 (s), ꢁ5.4 (s). IR:
n
2955, 2929, 2857, 2360, 2342, 1596, 1471, 1285, 1252, 1135, 1106,
1072, 836, 776, 680 cmꢁ1. HRMS calcd for C14H23ClNaO2Siþ
[MþNa]þ: 309.1048, found: 309.1038.
1H NMR (400 MHz, CDCl3)
d
7.11 (t, J¼8.3 Hz,1H), 7.06e7.02 (m, 2H),
6.81 (ddd, J¼8.2, 2.2,1.3 Hz,1H), 5.68e5.38 (m, 2H), 3.92 (t, J¼6.9 Hz,
2H), 2.52e2.39 (m, 2H), 2.10e1.96 (m, 2H), 0.97 (t, J¼7.5 Hz, 3H). 13
C
NMR (101 MHz, CDCl3) d 159.9 (s),135.1 (s), 130.5 (s), 124.3 (s), 123.7
4.2.2. (E)-1-(But-2-en-1-yloxy)-3-chlorobenzene (6m). Compound
6m was obtained in 91% yield as colorless oil (1.67 g) from 3-
chlorophenol and 2-buten-1-ol (cis:trans¼1:19), Rf¼0.3 (Hexane);
(s),122.9 (s),117.9 (s),113.6 (s), 68.1 (s), 32.5 (s), 25.8 (s),13.9 (s). IR: n
2962.45, 2931.60, 2872.51, 1589.33, 1572.77, 1477.33, 1467.23,
1423.67, 1387.51, 1304.40, 1284.04, 1243.85, 1228.25, 1064.51,
1030.13, 991.36, 967.39, 864.47, 763.80, 680.07 cmꢁ1. HRMS calcd for
1H NMR (400 MHz, CDCl3)
d
7.17 (ddd, J¼8.3, 7.8, 0.4 Hz, 1H),
6.93e6.87 (m, 2H), 6.78 (ddd, J¼8.4, 2.4, 1.0 Hz, 1H), 5.90e5.80 (m,
C12H15BrO [M]: 254.0306, found: 254.0301.
1H), 5.74e5.65 (m, 1H), 4.44e4.40 (m, 2H), 1.75 (ddd, J¼6.4, 2.7,
1.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d
159.4 (s), 134.8 (s), 131.0 (s),
4.2.8. (Z)-1-Bromo-3-(hex-3-en-1-yloxy)benzene (6u). Compound
6u was obtained in 81% yield as a colorless oil (1.0335 g) from 3-
bromophenol and (Z)-hex-3-en-1-ol, Rf¼0.8 (Hexane/EtOAc¼5:1);
130.1 (s), 125.5 (s), 120.8 (s), 115.0 (s), 113.3 (s), 68.9 (s), 17.9 (s). IR:
n
2968, 2094, 1636, 1596, 1477, 1377, 1306, 1282, 1227, 1009, 965, 765,
680 cmꢁ1. HRMS calcd for C10H11ClO [M]: 182.0498, found:
182.0497.
1H NMR (400 MHz, CDCl3)
d 7.13e7.08 (m, 1H), 7.07e7.05 (m, 1H),
7.04e7.02 (m, 1H), 6.80 (ddd, J¼8.2, 2.4, 1.2 Hz, 1H), 5.57e5.34 (m,
2H), 3.91 (t, J¼6.9 Hz, 2H), 2.55e2.47 (m, 2H), 2.13e2.02 (m, 2H),
4.2.3. 1-Chloro-3-((3-methylbut-3-en-1-yl)oxy)benzene
(6o). Compound 6o was obtained in 96% yield as colorless oil (1.90 g)
from 3-chlorophenol and 3-methyl-3-buten-1-ol, Rf¼0.3 (Hexane);
0.97 (t, J¼7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 159.8 (s), 134.5
(s), 130.5 (s), 123.9 (s), 123.70 (s), 122.9 (s), 117.8 (s), 113.5 (s), 67.7
(s), 27.3 (s), 20.8 (s), 14.4 (s). IR:
n 3010.01, 2963.14, 2931.95,
1H NMR (400 MHz, CDCl3)
d
7.20e7.14 (m, 1H), 6.93e6.87 (m, 2H),
2873.44, 1590.34, 1573.28, 1477.45, 1467.58, 1423.93, 1384.86,
1324.35, 1243.67, 1228.67, 1064.73, 1031.03, 928.69, 855.47, 845.36,
764.17, 726.61, 680.08 cmꢁ1. HRMS calcd for C12H15BrO [M]:
254.0306, found: 254.0304.
6.80e6.75 (m, 1H), 4.85e4.82 (m, 1H), 4.81e4.76 (m, 1H), 4.04 (t,
J¼6.8 Hz, 2H), 2.48 (t, J¼6.8 Hz, 2H), 1.79 (d, J¼0.9 Hz, 3H). 13C NMR
(101 MHz, CDCl3)
d 159.6 (s), 141.9 (s), 134.8 (s), 130.1 (s), 120.8 (s),
114.9 (s),113.1 (s),112.1 (s), 66.6 (s), 37.0 (s), 22.8 (s). IR: n 3077, 2936,
1651, 1679, 1470, 1428, 1387, 1263, 1231, 1071, 1042, 864, 840,
4.2.9. 1-Bromo-3-((2-methylenedecyl)oxy)benzene (6w). Compound
6w was obtained in 98% yield as a colorless oil (1.0335 g) from 3-
bromophenol and 2-methylenedecan-1-ol,31 Rf¼0.95 (Hexane/
764 cmꢁ1. HRMS calcd for C11H13ClO [M]: 196.0655, found: 196.0656.
4.2.4. 1-Bromo-3-(hex-3-yn-1-yloxy)benzene (6p). Compound 6p
was obtained in 76% yield as a light yellow oil (1.15 g) from 3-
bromophenol and 3-hexyn-1-ol, Rf¼0.8 (Hexane/EtOAc¼5:1); 1H
EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
7.14 (dd, J¼10.9, 5.5 Hz,1H),
d
7.10e7.07 (m, 2H), 6.86 (ddd, J¼8.1, 2.4, 1.2 Hz, 1H), 5.12 (d, J¼1.3 Hz,
1H), 5.01 (d, J¼1.3 Hz, 1H), 4.44 (s, 2H), 2.18e2.10 (m, 2H), 1.49 (dt,
J¼14.9, 7.4 Hz, 2H), 1.38e1.22 (m, 10H), 0.89 (t, J¼6.9 Hz, 3H). 13C
NMR (400 MHz, CDCl3) d 7.15e7.05 (m, 3H), 6.85e6.80 (m, 1H), 4.01
(t, J¼7.2 Hz, 2H), 2.61 (t, J¼7.2, 2.4 Hz, 2H), 2.16 (qt, J¼7.5, 2.4 Hz, 2H),
NMR (101 MHz, CDCl3) d 159.7 (s), 144.4 (s), 130.5 (s), 123.9 (s), 122.9
1.11 (t, J¼7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d
159.3 (s),130.5 (s),
(s), 118.2 (s), 113.6 (s), 112.0 (s), 71.0 (s), 33.2 (s), 32.1 (s), 29.7 (s), 29.6
(s), 29.5 (s), 27.7 (s), 22.9 (s), 14.3 (s). IR: 2925.69, 2854.50, 1653.98,
124.0 (s), 122.8 (s), 117.9 (s), 113.6 (s), 83.6 (s), 74.8 (s), 66.8 (s), 19.7
n
(s), 14.1 (s), 12.4 (s). IR:
n
2108, 1652, 1468, 1284, 1229, 1036 cmꢁ1
.
1589.36, 1573.78, 1475.15, 1303.47, 1283.61, 1224.44, 1020.29, 903.21,
763.62, 679.35 cmꢁ1. HRMS calcd for C17H25OBr [M]: 324.1089,
found: 324.1086.
HRMS calcd for C12H13BrO [M]: 252.0150, found: 252.0154.
4.2.5. 1-Chloro-3-((5-phenylpent-4-yn-1-yl)oxy)benzene
(6q). Compound 6q was obtained in 98% yield as a colorless oil
(836 mg) from 3-chlorophenol and 5-phenylpent-4-yn-1-ol, Rf¼0.8
4.3. General procedure B: SN2 reaction
(Hexane); 1H NMR (400 MHz, CDCl3)
d
7.41e7.36 (m, 2H), 7.29e7.24
To a 100 mL flask equipped with a stir bar were added 3-
(m, 3H), 7.18 (t, J¼8.4 Hz, 1H), 6.93e6.90 (m, 2H), 6.80 (ddd, J¼8.4,
bromophenol (10 mmol, 1 equiv), K2CO3 (50 mmol, 5 equiv), KI
2.4, 1.0 Hz, 1H), 4.09 (t, J¼6.1 Hz, 2H), 2.61 (t, J¼6.9 Hz, 2H),
(30 mmol,
3 equiv) corresponding allylic halide (25 mmol,
2.10e2.03 (m, 2H). 13C NMR (101 MHz, CDCl3)
d 159.6 (s), 134.8 (s),
2.5 equiv), and acetone (30 mL). The reaction was then heated to

P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
4141
reflux for ca. 12 h before quenching with aqueous NH4Cl. The
aqueous phase was extracted with ethyl acetate (30 mLꢂ3). The
combined organic extract was concentrated under reduced pres-
sure and purified by column chromatography on silica gel to afford
the following compounds.
4.6 Hz, 1H), 3.00 (ddt, J¼14.5, 1.7, 0.8 Hz, 1H), 2.21 (d, J¼9.6 Hz, 1H).
13C NMR (101 MHz, CDCl3)
153.5 (s), 144.0 (s), 137.4 (s), 131.4 (s),
131.0 (s), 128.5 (s), 127.9 (s), 127.2 (s), 115.9 (s), 114.9 (s), 71.1 (s), 70.8
d
(s), 42.4 (s). IR:
n 3071, 2956, 2929, 1719, 1600, 1581, 1475, 1390,
1350, 1265,þ 1155, 11þ08, 1032, 845 cmꢁ1
. HRMS calcd for
C
15H14NaO2 [MþNa] : 249.0891, found: 249.0889. Mp (ꢀC):
4.3.1. 1-Bromo-3-((2-methylallyl)oxy)benzene (6l). Compound 6l
was obtained in 95% yield as a colorless oil (2.16 g) from 3-
bromophenol and 3-chloro-2-methyl-1-propene, Rf¼0.2 (Hex-
81e83.
4.4.3. 4,5-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7e). Compound 7e16b (CAS No.: 144493-71-0) was obtained in 53%
yield as a white solid (385 mg) from 6e, Rf¼0.1 (Hexane/
ane); 1H NMR (400 MHz, CDCl3)
d 7.14e7.04 (m, 3H), 6.84 (ddd,
J¼8.1, 2.4, 1.2 Hz, 1H), 5.09e5.05 (m, 1H), 5.00e4.97 (m, 1H), 4.40 (s,
2H), 1.83e1.79 (m, 3H). 13C NMR (101 MHz, CDCl3)
159.5 (s), 140.3
(s), 130.5 (s), 123.9 (s), 122.7 (s), 118.0 (s), 113.7 (s), 113.0 (s), 71.9 (s),
19.3 (s). IR:
2340, 1683, 1506, 1436, 1424, 1222, 1017 cmꢁ1. HRMS
d
EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
6.83 (d, J¼7.7 Hz,1H), 6.64
d
(dt, J¼7.7, 0.9 Hz, 1H), 5.33 (ddd, J¼10.3, 4.7, 1.9 Hz, 1H), 4.10 (s, 3H),
3.82 (s, 3H), 3.56 (ddd, J¼14.3, 4.7, 0.9 Hz, 1H), 2.94 (ddd, J¼14.3, 1.9,
1.0 Hz, 1H), 2.18 (d, J¼10.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)
n
calcd for C10H11BrO [M]: 225.9993, found: 225.9994.
d
147.6 (s), 144.5 (s), 134.7 (s), 130.6 (s), 115.5 (s), 114.2 (s), 70.4 (s),
4.3.2. 1-Bromo-3-((3-methylbut-2-en-1-yl)oxy)benzene
(6n). Compound 6n was obtained in 98% yield as a colorless oil
(2.36 g) from 3-bromophenol and 3,3-dimethylallyl bromide,
58.1 (s), 56.5 (s), 41.8 (s).
4.4.4. 2,5-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one
(7f). Compound 7f was obtained in 61% yield as a pale solid
(437 mg) from 6f, Rf¼0.1 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
Rf¼0.2 (Hexane); 1H NMR (400 MHz, CDCl3)
d 7.14e7.08 (m, 1H),
7.07e7.02 (m, 2H), 6.83 (ddd, J¼8.2, 2.3, 1.1 Hz, 1H), 5.49e5.42 (m,
1H), 4.47 (d, J¼6.8 Hz, 2H), 1.76 (d, J¼22.9 Hz, 6H). 13C NMR
CDCl3)
d
6.71 (d, J¼9.0 Hz, 1H), 6.65 (d, J¼9.0 Hz, 1H), 5.32 (ddd,
(101 MHz, CDCl3)
d
159.6 (s), 138.7 (s), 130.5 (s), 123.6 (s), 122.7 (s),
J¼9.0, 4.4, 1.4 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.71 (ddd, J¼13.9,
119.1 (s), 117.8 (s),113.8 (s), 65.0 (s), 25.8 (s), 18.2 (s). IR: n 2914,1587,
4.5, 0.4 Hz, 1H), 3.10 (ddd, J¼14.0, 1.8, 0.7 Hz, 1H), 2.33 (d, J¼9.3 Hz,
1475, 1383, 1283, 1224, 1064, 1000, 881, 764, 680 cmꢁ1. HRMS calcd
for C11H13BrO [M]: 240.0150, found: 240.0150.
1H). 13C NMR (101 MHz, CDCl3)
d 148.5 (s), 148.4 (s), 132.2 (s), 126.6
(s), 116.7 (s), 115.0 (s), 70.4 (s), 57.0 (s), 56.5 (s), 41.7 (s). IR:
n 3446,
2947, 2837, 1646, 1590, 1505, 1464, 1436, 1258, 1142,þ1109, 1077,
1047, 999, 811 cmꢁ1. HRMS calcd for C10H12NaO3 [MþH]þ:
203.0679, found: 203.0675. Mp (ꢀC): 72e75.
4.4. General procedure C: [2D2] coupling I
To a 100 mL flamed-dried flask equipped with stir bar and
a nitrogen-filled balloon was added THF (20 mL). The system was
cooled to 0 ꢀC with an ice-water bath before n-BuLi (2.5 M in
hexane, 6 mmol, 1.5 equiv) was added dropwise. Upon completion,
the system was warmed to rt and stirred for 16 h under nitrogen
atmosphere. At the same time, to a 30 mL flamed-dried flask
equipped with a stir bar and a nitrogen-filled balloon were added
2,2,6,6-tetramethylpiperidine (4.8 mmol, 1.2 equiv) and THF
(12 mL). After cooling to 0 ꢀC with an ice-water bath, n-BuLi (2.5 M
in hexane, 4.8 mmol, 1.2 equiv) was added dropwise and the re-
action was stirred at 0 ꢀC for 0.5 h. The previous 100 mL flask was
cooled to ꢁ78 ꢀC with an acetone-dry ice bath and benzyne pre-
cursor (4 mmol, 1.0 equiv) in THF (5 mL) was added before in situ
generated lithium tetramethylpiperidine was added dropwise. The
reaction was monitored by TLC and was quenched by adding
aqueous NH4Cl. The mixture was then warmed to rt and H2O
(30 mL) was added. The mixture was extracted with ethyl acetate
(30 mLꢂ3), washed with brine, and dried with Na2SO4. The com-
bined organic extract was concentrated under reduced pressure
and purified by column chromatography on silica gel to afford the
following compounds.
4.4.5. 5-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)bicyclo[4.2.0]octa-
1,3,5-trien-7-one (7g). Compound 7g was obtained in 16% yield as
a pale solid (47 mg) from 6g, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR
(400 MHz, CDCl3)
d
7.21e7.16 (m, 1H), 6.70 (dd, J¼7.8, 3.3 Hz, 2H),
5.32 (dd, J¼11.0, 6.3 Hz, 1H), 4.50 (ddd, J¼11.0, 5.7, 5.0 Hz, 1H), 4.17
(dt, J¼11.2, 4.2 Hz, 1H), 3.96 (t, J¼4.6 Hz, 2H), 3.54 (dd, J¼14.3,
4.5 Hz, 1H), 3.26 (d, J¼8.3 Hz, 1H), 2.99 (d, J¼14.4 Hz, 1H), 0.86 (s,
9H), 0.04 (d, J¼23.3 Hz, 6H). 13C NMR (101 MHz, CDCl3)
d 153.9 (s),
143.9 (s), 131.2 (s), 130.4 (s), 115.6 (s), 114.7 (s), 70.5 (s), 70.1 (s), 63.2
(s), 42.2 (s), 25.8 (s), 18.4 (s), ꢁ5.4 (d, J¼2.9 Hz). IR:
n 3223, 2955,
2929, 2857, 1605, 1583, 1475, 1453, 1263, 1130, 1097, 1064, 949, 832,
775 cmꢁ1. HRMS calcd for C16H24NaO3Siþ [MþNa]þ: 315.1543,
found: 315.1534. Mp (ꢀC): 49e51.
4.4.6. 5-((2-Methylallyl)oxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7l). Compound 7l was obtained in 61% yield as a yellow solid
(465 mg) from 6l, Rf¼0.1 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
CDCl3)
d
7.21 (dd, J¼8.3, 7.3 Hz, 1H), 6.75 (dd, J¼8.5, 0.7 Hz, 1H), 6.71
(d, J¼6.5 Hz, 1H), 5.28 (ddd, J¼10.0, 4.5, 1.8 Hz, 1H), 5.05 (td, J¼2.4,
1.6 Hz, 1H), 4.94 (dt, J¼2.7, 1.3 Hz, 1H), 4.65 (q, J¼13.1 Hz, 2H), 3.57
(dd, J¼14.5, 4.6 Hz, 1H), 2.98 (ddt, J¼14.5, 1.7, 0.8 Hz, 1H), 2.16 (d,
J¼9.7 Hz, 1H), 1.81 (d, J¼0.6 Hz, 3H). 13C NMR (101 MHz, CDCl3)
4.4.1. 5-Methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol (7a). Compound
7a18 (CAS No.: 66947-61-3) was obtained as a white solid from 6a in
71% yield (425 mg) and 6b in 48% yield (287 mg), Rf¼0.15 (Hexane/
d
153.5 (s), 143.9 (s), 141.3 (s), 131.3 (s), 130.8 (s), 115.7 (s), 114.7 (s),
112.0 (s), 72.7 (s), 70.8 (s), 42.4 (s), 19.3 (s). IR:
n 3286, 2919, 1602,
EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
d
7.22 (dd, J¼8.3, 7.3 Hz,
1582, 1475, 1384, 1268, þ1261, 1105, 1045, 900 cmꢁ1. HRMS calcd for
þ
1H), 6.75e6.69 (m, 2H), 5.36 (ddd, J¼9.6, 4.5, 1.8 Hz, 1H), 3.97 (s,
3H), 3.60 (dd, J¼14.5, 4.5 Hz, 1H), 3.00 (ddt, J¼14.5, 1.7, 0.7 Hz, 1H),
C
12H14NaO2 [MþNa] : 213.0891, found: 213.0893. Mp (ꢀC):
47e49.
2.29 (d, J¼9.7 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d 154.3 (s), 144.1
(s), 131.3 (s), 130.9 (s), 115.6 (s), 113.8 (s), 70.7 (s), 56.9 (s), 42.5 (s).
4.4.7. (E)-5-(But-2-en-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7m). Compound 7m was obtained in 64% yield as a white solid
(490 mg) from 6m, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR
4.4.2. 5-(Benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7c). Compound 7c was obtained as a white solid from 6c in 52%
yield (470 mg) and 6d in 70% yield (637 mg), Rf¼0.2 (Hexane/
(400 MHz, CDCl3)
d
7.20 (dd, J¼8.3, 7.3 Hz, 1H), 6.75e6.69 (m, 2H),
5.91e5.80 (m, 1H), 5.76e5.66 (m, 1H), 5.30 (ddd, J¼9.6, 4.5, 1.7 Hz,
1H), 4.76e4.58 (m, 2H), 3.57 (dd, J¼14.4, 4.6 Hz, 1H), 3.06e2.90 (m,
1H), 2.23 (d, J¼9.7 Hz, 1H), 1.73 (dd, J¼6.4, 1.4 Hz, 3H). 13C NMR
EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
d 7.46e7.21 (m, 6H), 6.81
(dd, J¼8.5, 0.7 Hz, 1H), 6.74 (dd, J¼7.2, 0.5 Hz, 1H), 5.32 (dd, J¼39.8,
12.2 Hz, 2H), 5.22 (ddd, J¼9.6, 4.6, 1.9 Hz, 1H), 3.58 (dd, J¼14.5,
(101 MHz, CDCl3)
d 153.4 (s), 144.0 (s), 131.3 (s), 130.9 (s), 130.3 (s),

4142
P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
126.3 (s), 115.6 (s), 114.6 (s), 70.9 (s), 70.0 (s), 42.4 (s), 17.9 (s). IR:
n
1474.30, 1198.14, 1139.22, 1044.28, 770.46 cmꢁ1. HRMS calcd for
C11H12O2 [M]: 176.0837, found: 176.0834.
2956, 1653, 1603, 1582, 1457, 1262, 1137, 1106, 1046, 965, 775 cmꢁ1
.
HRMS calcd for C12H14NaO2 [MþNa]þ: 213.0891, found: 213.0888.
Mp (ꢀC): 78e80.
4.4.13. (E)-5-((2-Phenylbut-2-en-1-yl)oxy)bicyclo[4.2.0]octa-1,3,5-
trien-7-ol (7s). Compound 7s was obtained in 60% yield as colorless
oil (158.9 mg) from 6s, Rf¼0.1 (Hexane/EtOAc¼5:1); 1H NMR
4.4.8. 5-((3-Methylbut-2-en-1-yl)oxy)bicyclo[4.2.0]octa-1,3,5-trien-
7-ol (7n). Compound 7n was obtained in 56% yield as a light yellow
solid (460 mg) from 6n, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR
(400 MHz, CDCl3)
d 7.42e7.26 (m, 5H), 7.26e7.19 (m, 1H), 6.75 (dd,
J¼13.3, 7.8 Hz, 2H), 6.00 (q, J¼6.9 Hz, 1H), 5.28 (d, J¼12.1 Hz, 1H),
4.94 (dd, J¼52.3, 12.0 Hz, 2H), 3.55 (dd, J¼14.4, 4.5 Hz, 1H), 2.96 (d,
J¼14.4 Hz, 1H), 2.69 (s, 1H), 1.72 (d, J¼6.9 Hz, 3H). 13C NMR
(400 MHz, CDCl3)
d 7.22e7.17 (m, 1H), 6.74e6.68 (m, 2H), 5.48 (t,
J¼6.8 Hz, 1H), 5.32 (ddd, J¼14.4, 8.8, 5.6 Hz, 1H), 4.74 (ddd, J¼65.1,
11.5, 6.8 Hz, 2H), 3.58 (dd, J¼14.4, 4.5 Hz, 1H), 3.02e2.95 (m, 1H),
2.23 (d, J¼9.7 Hz, 1H), 1.76 (d, J¼17.5 Hz, 6H). 13C NMR (101 MHz,
(101 MHz, CDCl3)
d 153.5 (s), 144.0 (s), 138.3 (s), 137.2 (s), 131.3 (s),
131.1 (s), 128.8 (s), 128.2 (s), 127.1 (s), 125.9 (s), 115.7 (s), 114.8 (s),
74.1 (s), 70.7 (s), 42.3 (s), 14.7 (s). IR: 3371.38, 3057.22, 2924.24,
CDCl3)
d
153.6 (s), 144.0 (s), 138.4 (s), 131.3 (s), 131.0 (s), 119.9 (s),
n
115.5 (s), 114.7 (s), 71.0 (s), 66.1 (s), 42.4 (s), 25.8 (s), 18.2 (s). IR:
n
1603.75, 1582.78, 1493.84, 1473.32, 1377.93, 1258.18, 1197.55,
1179.16, 1140.54, 1088.88, 1042.44, 980.88, 912.35, 768.85, 728.36,
2967, 2925, 1605, 1582, 1469, 1384, 1251, 1199, 1043, 976, 767 cmꢁ1
.
HRMS calcd for C13H16NaO2þ [MþNa]þ: 227.1048, found: 227.1044.
702.35 cmꢁ1. HRMS calcd for C18H18NaO2 [MþNa]þ: 289.1199,
þ
Mp (ꢀC): 60e62.
found: 289.1200.
4.4.9. 5-((3-Methylbut-3-en-1-yl)oxy)bicyclo[4.2.0]octa-1,3,5-trien-
7-ol (7o). Compound 7o was obtained in 66% yield as a white solid
(661 mg) from 6o, Rf¼0.1 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
4.4.14. (E)-5-(Hex-3-en-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7t). Compound 7t was obtained in 25% yield as light yellow solid
(54.2 mg) from 6t, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
CDCl3)
d
7.20 (dd, J¼8.8, 7.1 Hz, 1H), 6.73e6.70 (m, 1H), 6.69 (s, 1H),
CDCl3)
d
7.19 (dd, J¼8.4, 7.2 Hz, 1H), 6.71 (d, J¼3.4 Hz, 1H), 6.69 (d,
5.32 (ddd, J¼9.7, 4.5, 1.8 Hz, 1H), 4.84e4.81 (m, 1H), 4.80e4.78 (m,
1H), 4.33 (ddt, J¼55.1, 9.7, 6.8 Hz, 2H), 3.59 (dd, J¼14.5, 4.5 Hz, 1H),
2.99 (ddt, J¼14.5, 1.7, 0.8 Hz, 1H), 2.47 (t, J¼6.8 Hz, 2H), 2.15 (d,
J¼1.5 Hz, 1H), 5.65e5.41 (m, 2H), 5.29 (dd, J¼7.8, 3.9 Hz, 1H), 4.20
(ddt, J¼46.2, 9.5, 6.8 Hz, 2H), 3.56 (dd, J¼14.4, 4.5 Hz, 1H), 2.97 (d,
J¼14.4 Hz, 1H), 2.44 (qd, J¼6.7, 1.0 Hz, 2H), 2.31 (s, 1H), 2.02 (qdd,
J¼7.4, 6.3, 1.2 Hz, 2H), 0.97 (t, J¼7.5 Hz, 3H). 13C NMR (101 MHz,
J¼9.7 Hz, 1H), 1.79 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 153.6 (s),
144.0 (s),142.3 (s),131.3 (s),130.9 (s),115.5 (s),114.6 (s),111.9 (s), 70.9
CDCl3) d 153.7 (s), 144.0 (s), 134.8 (s), 131.3 (s), 130.9 (s), 124.4 (s),
(s), 67.8 (s), 42.5 (s), 37.4 (s), 22.9 (s). IR:
n
2964, 2919, 1647, 1606,
115.5 (s), 114.6 (s), 70.9 (s), 69.2 (s), 42.4 (s), 32.8 (s), 25.7 (s), 13.7
1469, 1402, 1274, 1140þ, 1108, 1054, 893, 765 cmꢁ1. HRMS calcd for
(s). IR: n 3327.06, 2961.45, 2925.77, 1604.48, 1583.10, 1465.81,
þ
C
13H16NaO2 [MþNa] : 227.1048 found: 227.1047. Mp (ꢀC): 61e63.
1260.99, 1139.46, 1046.37, 968.37, 767.96 cmꢁ1. HRMS calcd for
þ
C
14H18NaO2 [MþNa]þ: 241.1199, found: 241.1204. Mp (ꢀC):
4.4.10. 5-(Hex-3-yn-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7p). Compound 7p was obtained in 51% yield as a light yellow
solid (439 mg) from 6p, Rf¼0.1 (Hexane/EtOAc¼5:1); 1H NMR
37e39.
4.4.15. (Z)-5-(Hex-3-en-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7u). Compound 7u was obtained in 27% yield as light yellow solid
(59.0 mg) from 6u, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
(400 MHz, CDCl3)
d
7.20 (dd, J¼8.4, 7.3 Hz, 1H), 6.72 (dd, J¼7.8,
4.0 Hz, 2H), 5.33 (ddd, J¼9.4, 4.5, 1.8 Hz,1H), 4.37e4.18 (m, 2H), 3.58
(dd, J¼14.4, 4.6 Hz, 1H), 2.99 (ddt, J¼14.5, 1.7, 0.8 Hz, 1H), 2.64e2.58
(m, 2H), 2.28 (d, J¼9.4 Hz, 1H), 2.15 (qt, J¼7.5, 2.4 Hz, 2H), 1.09 (t,
CDCl3)
d
7.23e7.17 (m, 1H), 6.69 (d, J¼7.6 Hz, 2H), 5.56e5.37 (m,
2H), 5.30 (s, 1H), 4.19 (ddt, J¼48.3, 9.3, 6.9 Hz, 2H), 3.57 (dd, J¼14.4,
4.5 Hz, 1H), 2.97 (dd, J¼14.4, 0.8 Hz, 1H), 2.50 (q, J¼7.0 Hz, 2H), 2.25
J¼7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 153.3 (s), 144.0 (s), 131.3
(s), 130.9 (s), 115.8 (s), 114.6 (s), 83.4 (s), 75.3 (s), 70.8 (s), 67.8 (s),
(d, J¼8.0 Hz, 1H), 2.07 (p, J¼7.5 Hz, 2H), 0.97 (t, J¼7.5 Hz, 3H). 13
C
42.4 (s), 20.1 (s), 14.1 (s), 12.41 (s). IR:
n
2106, 1645, 1466, 1259, 1140,
NMR (101 MHz, CDCl3) d 153.6 (s), 144.0 (s), 134.3 (s), 131.3 (s), 130.9
1051, 770 cmꢁ1. HRMS calcd for C14H16NaO2 [MþNa]þ: 239.1048,
(s), 124.1 (s), 115.5 (s), 114.5 (s), 70.9 (s), 68.9 (s), 42.5 (s), 27.6 (s),
20.7 (s), 14.2 (s). IR: 3327.95, 3009.99, 2962.18, 2930.15, 2874.42,
found: 239.1045. Mp (ꢀC): 42e45.
n
1604.82, 1583.41, 1478.15, 1466.83, 1387.75, 1261.52, 1197.50,
þ
4.4.11. 5-((5-Phenylpent-4-yn-1-yl)oxy)bicyclo[4.2.0]octa-1,3,5-
trien-7-ol (7q). Compound 7q was obtained in 32% yield as a white
solid (176 mg) from 6q, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR
1140.13,þ1049.18, 770.12, 730.86 cmꢁ1. HRMS calcd for C14H18NaO2
[MþNa] : 241.11990, found: 241.12040. Mp (ꢀC): 35e37.
(400 MHz, CDCl3)
d
7.41e7.16 (m, 6H), 6.75e6.67 (m, 2H), 5.33 (ddd,
4.4.16. 5-(But-3-en-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7v). Compound 7v was obtained in 27% yield as light yellow solid
(51.3 mg) from 6v, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
J¼9.7, 4.5, 1.8 Hz, 1H), 4.36 (ddt, J¼51.3, 9.8, 6.1 Hz, 2H), 3.58 (dd,
J¼14.5, 4.6 Hz, 1H), 3.04e2.89 (m, 1H), 2.61 (t, J¼7.0 Hz, 2H), 2.20 (d,
J¼9.7 Hz, 1H), 2.13e1.97 (m, 2H). 13C NMR (101 MHz, CDCl3)
d
153.6
CDCl3)
d
7.20 (dd, J¼8.4, 7.1 Hz, 1H), 6.71 (dd, J¼3.8, 3.1 Hz, 1H), 6.69
(s),144.1 (s),131.5 (s),131.3 (s),130.9 (s),128.2 (s),127.6 (s),123.7 (s),
115.6 (s),114.6 (s), 89.2 (s), 81.1 (s), 70.9 (s), 67.8 (s), 42.5 (s), 28.8 (s),
(d, J¼0.6 Hz, 1H), 5.89 (ddt, J¼17.0, 10.3, 6.7 Hz, 1H), 5.28 (d,
J¼2.6 Hz, 1H), 5.19e5.12 (m, 1H), 5.11e5.05 (m, 1H), 4.25 (ddt,
J¼50.0, 9.6, 6.7 Hz, 2H), 3.56 (dd, J¼14.5, 4.5 Hz, 1H), 2.97 (d,
J¼14.9 Hz, 1H), 2.57e2.44 (m, 2H), 2.38 (s, 1H). 13C NMR (101 MHz,
16.1 (s). IR:
n
2919, 2359, 2339, 1384, 126þ7, 1261, 1051, 743, 692,
668 cmꢁ1. HRMS calcd for C19H18NaO2 [MþNa]þ: 301.1204,
found: 301.1200. Mp (ꢀC): 87e89.
CDCl3)
d 153.6 (s), 144.0 (s), 134.5 (s), 131.3 (s), 130.9 (s), 117.0 (s),
115.6 (s), 114.6 (s), 70.9 (s), 68.6 (s), 42.4 (s), 33.9 (s). IR:
n 3297.24,
4.4.12. 5-(Allyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7r). Compound 7r was obtained in 17% yield as a light yellow oil
(30.1 mg) from 6r, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
2954.81, 2920.34, 1604.23, 1584.37, 1478.79, 1467.52, 1391.45,
1265.78, 1139.87, 1102.64, 1053.98, 992.70, 914.94, 773.25 cmꢁ1
.
HRMS calcd for C12H14O2 [M]: 190.0994, found: 190.0992. Mp (ꢀC):
CDCl3)
d
7.22 (dd, J¼8.3, 7.2 Hz, 1H), 6.74 (dd, J¼10.8, 7.8 Hz, 2H),
46e48.
6.05 (ddt, J¼17.3, 10.4, 5.1 Hz, 1H), 5.40 (ddd, J¼17.3, 3.3, 1.6 Hz, 1H),
5.32e5.21 (m, 2H), 4.87e4.64 (m, 2H), 3.58 (dd, J¼14.5, 4.6 Hz, 1H),
4.4.17. 5-((2-Methylenedecyl)oxy)bicyclo[4.2.0]octa-1(6),2,4-trien-
7-ol (7w). Compound 7w was obtained in 48% yield as white solid
(136.9 mg) from 6w, Rf¼0.4 (Hexane/EtOAc¼5:1); 1H NMR
3.05e2.93 (m, 1H), 2.47 (s, 1H). 13C NMR (101 MHz, CDCl3)
d 153.3
(s), 144.0 (s), 133.6 (s), 131.4 (s), 130.8 (s), 117.2 (s), 115.8 (s), 114.7 (s),
70.8 (s), 69.9 (s), 42.4 (s). IR: 3331.28, 2925.33, 1604.11, 1584.10,
n
(400 MHz, CDCl3)
d
7.20 (dd, J¼8.4, 7.2 Hz, 1H), 6.72 (dd, J¼15.9,

P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
4143
7.6 Hz, 2H), 5.33e5.20 (m, 1H), 5.12e5.04 (m, 1H), 4.93 (t, J¼9.9 Hz,
1H), 4.67 (dd, J¼33.1, 13.0 Hz, 2H), 3.56 (dd, J¼14.4, 4.6 Hz, 1H),
3.00e2.94 (m, 1H), 2.32 (d, J¼9.5 Hz, 1H), 2.19e2.04 (m, 2H),
1.56e1.38 (m, 2H), 1.41e1.20 (m, 10H), 0.87 (t, J¼6.9 Hz, 3H). 13C
flame-dried flask equipped with a stir bar and a nitrogen-filled
balloon were added THF (30 mL), benzyne precursor (1 equiv),
and corresponding ketene silyl acetals9 (1.5 equiv) and was cooled
to ꢁ78 ꢀC with an acetone-dry ice bath before in situ generated
lithium tetramethylpiperidine was added dropwise. The reaction
was monitored and aqueous NH4Cl was added upon disappearance
of the benzyne precursor. After warming to rt, the reaction mixture
was extracted with ethyl acetate (30 mLꢂ3), washed with brine,
and concentrated under reduced pressure. Acetonitrile (30 mL) was
added to the concentrated reaction system and cooled to 0 ꢀC with
an ice-water bath followed by slow addition of hydrofluoric acid
(27.6 M, 10 equiv). Upon completion, the reaction was heated to
40 ꢀC overnight before water (100 mL) was added. The mixture was
extracted with ethyl acetate (30 mLꢂ3), washed with brine, and
dried with Na2SO4. The combined organic extract was concentrated
under reduced pressure and purified by column chromatography
on silica gel to afford the following compounds.
NMR (101 MHz, CDCl3) d 153.5 (s), 145.5 (s), 144.0 (s), 131.3 (s), 131.0
(s),115.7 (s),114.7 (s),111.1 (s), 71.9 (s), 70.8 (s), 42.3 (s), 33.0 (s), 31.9
(s), 29.5 (s), 29.5 (s), 29.3 (s), 27.6 (s), 22.7 (s), 14.2 (s). IR: 3326.98,
n
2925.26, 2854.79, 1604.56, 1584.60, 1474.37, 1260.18, 1197.28,
1139.77, 1097.55, 1045.34þ, 900.06, 769.66 cmꢁ1
. HRMS calcd
þ
for C19H28NaO2 [MþNa] : 311.1982, found: 311.1982. Mp (ꢀC):
39e40.
4.5. General procedure D: [2D2] coupling II
To a 100 mL flamed-dried flask equipped with stir bar and
a nitrogen-filled balloon was added THF (20 mL). The system was
cooled to 0 ꢀC with an ice-water bath before n-BuLi (2.5 M in
hexane, 6 mmol, 1.5 equiv) was added dropwise. Upon completion,
the system was warmed to rt and stirred for 16 h under nitrogen
atmosphere. At the same time, to a 30 mL flamed-dried flask
equipped with a stir bar and a nitrogen-filled balloon were added
2,2,6,6-tetramethylpiperidine (4.8 mmol, 1.2 equiv) and THF
(12 mL). After cooled to 0 ꢀC with an ice-water bath, n-BuLi (2.5 M
in hexane, 4.8 mmol, 1.2 equiv) was added dropwise and the re-
action was stirred at 0 ꢀC for 0.5 h. The previous 100 mL flask was
cooled to ꢁ78 ꢀC with an acetone-dry ice bath and benzyne pre-
cursor (4 mmol, 1 equiv) in THF (5 mL) was added before in situ
generated lithium tetramethylpiperidine was added dropwise. The
reaction was stirred at ꢁ78 ꢀC for 3h and was warmed to rt before
quenching by adding aqueous NH4Cl (30 mL). The mixture was
extracted with ethyl acetate (30 mLꢂ3), washed with brine, and
dried with Na2SO4. The combined organic extract was concentrated
under reduced pressure and purified by column chromatography
on silica gel to afford the following compounds.
4.6.1. 5-(Benzyloxy)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-7-one
(9). Compound 9 was obtained as light yellow oil (271 mg) from 6d
and tert-butyl((1-methoxyprop-1-en-1-yl)oxy)dimethylsilane in
23% yield, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
d
7.48e7.30 (m, 6H), 7.02 (d, J¼7.0 Hz, 1H), 6.89 (d, J¼8.4 Hz, 1H),
5.45 (s, 2H), 4.21 (q, J¼7.2 Hz, 1H), 1.47 (d, J¼7.2 Hz, 3H). 13C NMR
(101 MHz, CDCl3)
d 189.3 (s), 157.0 (s), 152.6 (s), 137.8 (s), 136.4 (s),
130.7 (s), 128.5 (s), 128.2 (s), 127.9 (s), 116.7 (s), 114.2 (s), 74.0 (s),
58.3 (s), 15.0 (s). IR: 2964, 2927, 2360, 2342,1756, 1602, 1571, 1473,
n
1452, 1386, 1273, 1161, 1125, 991, 886, 795, 767, 748, 699 cmꢁ1
.
þ
HRMS calcd for
261.0879.
C
16H14NaO2
[MþNa]þ: 261.0886, found:
4.6.2. 8-Ethyl-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one
(10). Compound 10 was obtained as colorless oil (876 mg) from 6a
and tert-butyl((1-methoxybut-1-en-1-yl)oxy)dimethylsilane in
62% yield, Rf¼0.8 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
4.5.1. 5-(Benzyloxy)-2-chlorobicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7h). Compound 7h was obtained in 39% yield as a white solid
(202 mg) from 6h, Rf¼0.2 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
d
7.40 (dd, J¼8.4, 7.1 Hz, 1H), 6.99 (d, J¼7.1 Hz, 1H), 6.78 (d, J¼8.4 Hz,
1H), 4.13e4.06 (m, 4H), 1.98e1.72 (m, 2H), 1.04 (t, J¼7.5 Hz, 3H). 13
C
NMR (101 MHz, CDCl3) d 188.9 (s), 156.0 (s), 153.5 (s), 137.5 (s), 131.1
CDCl3)
d
7.44e7.28 (m, 5H), 7.14 (d, J¼8.9 Hz, 1H), 6.77 (d, J¼8.9 Hz,
(s), 116.0 (s), 114.6 (s), 65.0 (s), 59.7 (s), 23.3 (s), 11.5 (s). IR: n 2963,
1H), 5.33 (d, J¼12.2 Hz, 1H), 5.23 (d, J¼12.2 Hz, 1H), 5.15 (dd, J¼8.7,
3.7 Hz,1H), 3.55 (dd, J¼14.7, 4.5 Hz,1H), 2.98 (d, J¼14.8 Hz,1H), 2.25
2934, 2876, 2359, 2340, 1766, 1602, 1574, 1482, 1455, 1435, 1277,
þ
1157, 1123, 1020, 941, 799 cmꢁ1. HRMS calcd for C16H14NaO2
(d, J¼9.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d
152.5 (s), 140.7 (s),
[MþNa]þ: 261.0886, found: 261.0879.
137.1 (s), 132.0 (s), 130.9 (s), 128.6 (s), 128.0 (s), 127.1 (s), 119.7 (s),
117.2 (s), 71.4 (s), 69.8 (s), 41.0 (s). IR: n 3243, 2917, 2360, 2343, 1579,
1467, 1455, 1262, 1187, 1þ105, 1067, 996, 913, 826, 696 cmꢁ1. HRMS
calcd for C15H13ClNaO2 [MþNa]þ: 283.0496, found: 283.0497. Mp
(ꢀC): 85e88.
4.7. General procedure F: DMP oxidation I
A 10 mL flask equipped with a stir bar was charged with ben-
zocyclobutenols (0.2 mmol,1 equiv) and DMP (0.3 mmol, 1.5 equiv).
DCM (2 mL) was added and the reaction was monitored by TLC.
Upon disappearance of benzocyclobutenols, the reaction was di-
rectly purified by column chromatography on silica gel to afford the
following compounds.
4.5.2. 5-(Dimethylamino)bicyclo[4.2.0]octa-1,3,5-trien-7-ol
(7i). Compound 7i was obtained as an orange oil from 6i in 15%
(101 mg) and 6j in 16% (118 mg), Rf¼0.15 (Hexane/EtOAc¼5:1); 1H
NMR (400 MHz, CDCl3)
d
7.17 (dd, J¼8.5, 7.1 Hz, 1H), 6.46 (d,
J¼7.1 Hz, 1H), 6.41 (d, J¼8.5 Hz, 1H), 5.28 (ddd, J¼10.6, 4.4, 1.5 Hz,
1H), 3.53 (dd, J¼14.2, 4.4 Hz, 1H), 3.01 (s, 6H), 2.93e2.86 (m, 1H),
2.07 (d, J¼10.6 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d
146.3 (s), 143.8
4.7.1. 5-Methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (8a). Compound
8a12 (CAS No.: 66947-60-2) was obtained in 98% yield as a white
solid (45 mg) from 7a, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H NMR
(s), 131.1 (s), 130.6 (s), 111.4 (s), 110.4 (s), 71.9 (s), 42.0 (s), 40.3 (s). IR:
n
2109, 1640, 1501, 1439, 1355, 1230, 1041, 994, 696 cmꢁ1. HRMS
calcd for C10H13NNaOþ [MþNa]þ: 186.0895, found: 186.0892.
(400 MHz, CDCl3)
d
7.45e7.39 (m, 1H), 7.02 (d, J¼7.0 Hz, 1H), 6.79 (d,
J¼8.4 Hz, 1H), 4.12e4.09 (m, 3H), 3.91 (d, J¼0.6 Hz, 2H). 13C NMR
4.6. General procedure E: [2D2] coupling III
(101 MHz, CDCl3)
d 184.9 (s), 153.4 (s), 150.6 (s), 137.6 (s), 132.3 (s),
115.8 (s), 115.1 (s), 59.8 (s), 51.3 (s).
To a 30 mL flamed-dried flask equipped with stir bar and a ni-
trogen-filled balloon were added 2,2,6,6-tetramethylpiperidine
(1.2 equiv) and THF (12 mL). After cooled to 0 ꢀC with an ice-
water bath, n-BuLi (2.5 M in hexane, 1.2 equiv) was added drop-
wise and the reaction was stirred at 0 ꢀC for 0.5 h. To a 100 mL
4.7.2. 5-(Benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8c). Compound 8c8c (CAS No.: 169615-68-3) was obtained in 96%
yield as
a
white solid (44 mg) from 7c, Rf¼0.4 (Hexane/
EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
d 7.49e7.31 (m, 6H), 7.05

4144
P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
(dd, J¼7.1, 0.5 Hz, 1H), 6.89 (dd, J¼8.4, 0.5 Hz, 1H), 5.47 (s, 2H), 3.94
in 98% yield as a colorless oil (60 mg) from 7o, Rf¼0.6 (Hexane/
(s, 2H).
EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
7.39 (dd, J¼8.4, 7.1 Hz,1H),
d
6.98 (dd, J¼7.1, 0.6 Hz, 1H), 6.78 (dd, J¼8.4, 0.6 Hz, 1H), 4.84e4.78
(m, 2H), 4.48 (t, J¼6.7 Hz, 2H), 3.89 (s, 2H), 2.47 (t, J¼6.7 Hz, 2H),
1.79 (s, 3H).
4.7.3. 4,5-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one
(8e). Compound 8e12 (CAS No.: 81447-58-7) was obtained in 88%
yield as a white solid (46 mg) from 7e, Rf¼0.25 (Hexane/
EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
d
7.00 (d, J¼7.7 Hz,1H), 6.90
4.7.10. 5-(Hex-3-yn-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8p). Compound 8p7 was obtained in 93% yield as a colorless oil
(40 mg) from 7p, Rf¼0.4 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
(dt, J¼7.6, 0.9 Hz, 1H), 4.16 (s, 3H), 3.83 (s, 3H), 3.82 (d, J¼0.9 Hz,
2H).
CDCl3)
d
7.42 (dd, J¼8.4, 7.1 Hz, 1H), 7.11e6.94 (m, 1H), 6.84
4.7.4. 2,5-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one
(8f). Compound 8f10j (CAS No.: 75833-45-3) was obtained in 95%
yield as a white solid (51 mg) from 7f, Rf¼0.5 (Hexane/EtOAc¼5:1);
(dd, J¼8.4, 0.4 Hz, 1H), 4.45 (t, J¼6.6 Hz, 1H), 3.90 (s, 1H), 2.63
(t, J¼6.6, 2.4 Hz, 1H), 2.15 (qt, J¼7.5, 2.4 Hz, 1H), 1.10 (t,
J¼7.5 Hz, 1H).
1H NMR (400 MHz, CDCl3)
d
6.94 (d, J¼8.9 Hz, 1H), 6.73 (dt, J¼9.0,
0.8 Hz, 1H), 4.04 (s, 3H), 4.02 (d, J¼0.8 Hz, 2H), 3.85 (s, 3H). 13C NMR
4.7.11. 5-((5-Phenylpent-4-yn-1-yl)oxy)bicyclo[4.2.0]octa-1,3,5-
trien-7-one (8q). Compound 8q7 was obtained in 86% yield as
a light yellow oil (48 mg) from 7q, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H
(101 MHz, CDCl3)
d 184.6 (s), 148.4 (s), 147.6 (s), 133.3 (s), 132.2 (s),
124.4 (s), 117.6 (s), 59þ.7 (s), 56.8 (s), 50.6 (s). HRMS calcd for
þ
C
10H10NaO3 [MþNa] : 201.0522, found: 201.0519. Mp (ꢀC):
NMR (400 MHz, CDCl3) d 7.44e7.36 (m, 3H), 7.29e7.23 (m, 3H), 7.00
92e95.
(dd, J¼7.1, 0.6 Hz, 1H), 6.81 (dd, J¼8.4, 0.5 Hz, 1H), 4.53 (t, J¼6.0 Hz,
2H), 3.89 (s, 2H), 2.61 (t, J¼7.1 Hz, 2H), 2.11e2.04 (m, 2H).
4.7.5. 5-(Benzyloxy)-2-chlorobicyclo[4.2.0]octa-1,3,5-trien-7-one
(8h). Compound 8h was obtained in 98% yield as a light yellow
solid (82 mg) from 7h, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H NMR
4.7.12. 5-(Allyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8r). Compound 8r6a (CAS No.: 1402160-48-8) was obtained in 74%
yield as colorless oil (21.9 mg) from 7r, Rf¼0.6 (Hexane/EtOAc¼5:1);
(400 MHz, CDCl3)
d
7.45e7.30 (m, 6H), 6.86 (d, J¼8.8 Hz,1H), 5.42 (s,
2H), 3.96 (s, 2H). 13C NMR (101 MHz, CDCl3)
147.3 (s), 137.6 (s), 136.0 (s), 133.3 (s), 128.6 (s), 128.3 (s), 127.9 (s),
119.9 (s), 119.1 (s), 74.4 (s), 50.7 (s). IR: 2360, 2340, 1755, 1597,
d
182.7 (s), 151.1 (s),
1H NMR (400 MHz, CDCl3)
d
7.42 (dd, J¼8.4, 7.1 Hz, 1H), 7.01 (d,
J¼7.1 Hz, 1H), 6.83 (dd, J¼8.4, 0.5 Hz, 1H), 6.03 (ddt, J¼17.2, 10.6,
5.3 Hz,1H), 5.40 (dq, J¼17.3, 1.6 Hz, 1H), 5.25 (dq, J¼10.5, 1.4 Hz, 1H),
4.90 (dt, J¼5.4, 1.5 Hz, 1H), 3.90 (s, 1H).
n
1565, 1479, 1454, 1393, 1276,1259, 1110, 977, 918, 838, 756, 717, 694,
þ
668, 652 cmꢁ1
.
HRMS calcd for C15H11ClNaO2
[MþNa]þ:
281.0340, found: 281.0342. Mp (ꢀC): 115e117.
4.7.13. (E)-5-((2-Phenylbut-2-en-1-yl)oxy)bicyclo[4.2.0]octa-1,3,5-
trien-7-one (8s). Compound 8s was obtained in 93% yield as col-
orless oil (24.6 mg) from 7s, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H NMR
4.7.6. 5-((2-Methylallyl)oxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8l). Compound 8l6a (CAS No.: 1402160-41-1) was obtained in 98%
yield as a colorless oil (56 mg) from 7l, Rf¼0.6 (Hexane/EtOAc¼5:1);
(400 MHz, CDCl3)
d
7.41e7.23 (m, 6H), 6.98 (dd, J¼7.1, 0.4 Hz, 1H),
6.77 (dd, J¼8.4, 0.5 Hz, 1H), 5.99 (qd, J¼6.9, 6.0 Hz, 1H), 5.09 (s, 2H),
1H NMR (400 MHz, CDCl3)
d
7.43 (dd, J¼8.4, 7.1 Hz, 1H), 7.01 (d,
3.89 (s, 2H), 1.66 (dt, J¼7.0, 1.0 Hz, 3H). 13C NMR (101 MHz, CDCl3)
J¼6.5 Hz, 1H), 6.85 (d, J¼8.4 Hz, 1H), 5.09e5.03 (m, 1H), 4.98e4.92
d 185.0 (s), 152.3 (s), 150.4 (s), 138.1 (s), 137.6 (s), 136.7 (s), 132.4 (s),
(m, 1H), 4.83 (s, 2H), 3.90 (s, 2H), 1.83 (s, 3H).
128.8 (s), 128.1 (s), 127.4 (s), 127.0 (s), 116.5 (s), 115.0 (s), 77.1 (s), 51.1
(s), 14.7 (s). IR: 3056.04, 2917.02, 1760.50, 1600.41, 1571.43,
n
4.7.7. (E)-5-(But-2-en-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8m). Compound 8m was obtained in 94% yield as a light yellow
solid (54 mg) from 7m, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H NMR
1471.32, 1270.01, 1158.39, 1127.93, 1047.97, 975.00, 780.92,
þ
701.08 cmꢁ1. HRMS calcd for C18H16NaO2 [MþNa]þ: 287.1043,
found: 287.1033.
(400 MHz, CDCl3)
d
7.42 (dd, J¼8.4, 7.1 Hz, 1H), 7.01 (dd, J¼7.1,
0.5 Hz, 1H), 6.81 (dd, J¼8.4, 0.5 Hz, 1H), 5.90 (dqt, J¼15.2, 6.4, 1.2 Hz,
1H), 5.71 (dtq, J¼15.8, 6.3, 1.6 Hz, 1H), 4.86e4.82 (m, 2H), 3.91 (s,
2H), 1.74 (ddd, J¼6.5, 2.6, 1.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
4.7.14. (E)-5-(Hex-3-en-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8t). Compound 8t was obtained in 94% yield as colorless oil
(20.3 mg) from 7t, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H NMR
d
184.9 (s), 152.2 (s), 150.5 (s), 137.7 (s), 132.3 (s), 131.4 (s), 125.5 (s),
(400 MHz, CDCl3)
d
7.40 (dd, J¼8.4, 7.1 Hz, 1H), 6.98 (dd, J¼7.1,
116.3 (s), 114.9 (s), 72.8 (s), 51.1 (s), 17.9 (s). IR:
n
1758, 1610, 1573,
0.5 Hz, 1H), 6.79 (dd, J¼8.5, 0.5 Hz, 1H), 5.75e5.37 (m, 2H), 4.38 (t,
1472, 1455, 1381, 1264þ, 1158, 1118, 1050, 966, 751, 668 cmꢁ1. HRMS
calcd for C12H12NaO2 [MþNa]þ: 211.0730, found: 211.0725. Mp
(ꢀC): 41e43.
J¼6.7 Hz, 2H), 3.89 (s, 2H), 2.48e2.41 (m, 2H), 2.06e1.96 (m, 2H),
0.95 (t, J¼7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 185.0 (s), 152.6
(s), 150.5 (s), 137.6 (s), 134.9 (s), 132.3 (s), 124.2 (s), 116.2 (s), 114.8
(s), 72.1 (s), 51.1 (s), 32.5 (s), 25.6 (s), 13.7 (s). IR:
n 2962.01,
4.7.8. 5-((3-Methylbut-2-en-1-yl)oxy)bicyclo[4.2.0]octa-1,3,5-trien-
7-one (8n). Compound 8n was obtained in 77% yield as a colorless
oil (46 mg) from 7n, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H NMR
2930.58, 2359.68, 2340.51, 1770.32, 1604.37, 1572.65, 1476.29,
1460.12, 1275.54, 1158.85, 1128.56, 1052.18, 967.48, 782.60 cmꢁ1
.
þ
HRMS calcd for
239.1059.
C
14H16NaO2
[MþNa]þ: 239.1043, found:
(400 MHz, CDCl3)
d
7.40 (dd, J¼8.4, 7.1 Hz, 1H), 6.99 (dd, J¼7.1,
0.6 Hz, 1H), 6.79 (dd, J¼8.4, 0.6 Hz, 1H), 5.49 (tdt, J¼7.0, 2.8, 1.4 Hz,
1H), 4.87 (d, J¼7.0 Hz, 2H), 3.89 (t, J¼0.8 Hz, 2H), 1.77 (s, 3H), 1.75 (s,
4.7.15. (Z)-5-(Hex-3-en-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8u). Compound 8u was obtained in 97% yield as colorless oil
(21.0 mg) from 7u, Rf¼0.6 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
3H). 13C NMR (101 MHz, CDCl3)
d 185.0 (s), 152.4 (s), 150.5 (s), 139.5
(s), 137.6 (s), 132.4 (s), 119.0 (s), 116.3 (s), 114.9 (s), 69.1 (s), 51.1 (s),
25.8 (s), 18.3 (s). IR:
n
2918, 1772, 1678, 1601, 1583, 1476, 1389, 1352,
CDCl3)
d
7.40 (dd, J¼8.4, 7.1 Hz, 1H), 6.99 (dd, J¼7.1, 0.5 Hz, 1H), 6.78
1281, 1253, 1132, 1130, 1052, 97þ3, 945, 783, 754, 673, 577 cmꢁ1
.
(dd, J¼8.4, 0.5 Hz, 1H), 6.78 (dd, J¼8.4, 0.5 Hz, 1H), 5.55e5.38 (m,
1H), 4.37 (t, J¼6.6 Hz, 1H), 3.89 (s, 1H), 2.54e2.47 (m, 1H), 2.10e2.01
HRMS calcd for
225.0883.
C
13H14NaO2
[MþNa]þ: 225.0891, found:
(m, 1H), 0.96 (t, J¼7.5 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d 184.9 (s),
152.6 (s), 150.5 (s), 137.6 (s), 134.4 (s), 132.2 (s), 124.0 (s), 116.2 (s),
4.7.9. 5-((3-Methylbut-3-en-1-yl)oxy)bicyclo[4.2.0]octa-1,3,5-trien-
114.8 (s), 71.9 (s), 51.1 (s), 27.3 (s), 20.7 (s), 14.2 (s). IR:
2359.54, 1768.41, 1603.24, 1573.12, 1476.17, 1459.91, 1390.98,
n 2962.50,
7-one (8o). Compound 8o6a (CAS No.: 1402160-46-6) was obtained

P.-H. Chen et al. / Tetrahedron 70 (2014) 4135e4146
4145
1352.44, 1275.96, 1158.73, 1127.91, 1051.66, 782.46 cmꢁ1. HRMS
dried flask equipped with a stir bar and a nitrogen-filled balloon
were added 2,2,6,6-tetramethylpiperidine (24.16 g, 171 mmol,
28.86 mL, 1.5 equiv) and THF (120 mL). After cooled to 0 ꢀC with an
ice-water bath, n-BuLi (2.5 M in hexane, 68.4 mL, 171 mmol,
1.5 equiv) was added dropwisely and the reaction was stirred at
þ
calcd for C14H16NaO2 [MþNa]þ: 239.1043, found: 239.1050.
4.7.16. 5-(But-3-en-1-yloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8v). Compound 8v6b (CAS No.: 1415357-68-4) was obtained in 92%
yield as colorless oil (17.3 mg) from 7v, Rf¼0.6 (Hexane/EtOAc¼5:1);
0
ꢀC for 0.5 h. The previous 1000 mL flask was cooled to ꢁ78 ꢀC
1H NMR (400 MHz, CDCl3)
d
7.40 (dd, J¼8.4, 7.1 Hz, 1H), 6.99 (dd,
with an acetone-dry ice bath and 6d (30 g, 114 mmol, 1 equiv) in
THF (120 mL) was added before in situ generated lithium tetra-
methylpiperidine was added dropwisely. The reaction was stirred
at ꢁ78 ꢀC for 0.5 h and was quenched by adding aqueous NH4Cl.
The mixture was then warmed to rt and H2O (200 mL) was added.
The mixture was extracted with ethyl acetate (200 mLꢂ3), washed
with brine, and dried with Na2SO4. The combined organic extract
was concentrated under reduced pressure and used directly
without purification.
J¼7.1, 0.5 Hz, 1H), 6.79 (dd, J¼8.4, 0.5 Hz, 1H), 5.89 (ddt, J¼17.0, 10.3,
6.7 Hz, 1H), 5.15 (ddd, J¼17.2, 3.4, 1.6 Hz, 1H), 5.11e5.06 (m, 1H),
4.43 (t, J¼6.5 Hz, 2H), 3.89 (s, 2H), 2.52 (qt, J¼6.6, 1.4 Hz, 2H).
4.7.17. 5-((2-Methylenedecyl)oxy)bicyclo[4.2.0]octa-1(6),2,4-trien-
7-one (8w). Compound 8w was obtained in 86% yield as colorless
oil (37.2 mg) from 7w, Rf¼0.75 (Hexane/EtOAc¼5:1); 1H NMR
(400 MHz, CDCl3)
d
7.41 (dd, J¼8.4, 7.1 Hz, 1H), 7.00 (dd, J¼7.0,
0.4 Hz, 1H), 6.83 (dd, J¼8.4, 0.5 Hz, 1H), 5.11e5.05 (m, 1H),
4.97e4.91 (m, 1H), 4.84 (s, 2H), 3.89 (s, 2H), 2.20e2.05 (m, 2H),
1.52e1.39 (m, 2H), 1.37e1.18 (m, 10H), 0.86 (t, J¼6.9 Hz, 3H). 13C
To a 1000 mL flamed-dried flasks equipped with a stir bar and
a nitrogen-filled balloon was added oxalyl chloride (21.84 g,
172 mmol, 1.5 equiv) and DCM (200 mL). The flask was cooled to
ꢁ78 ꢀC and DMSO (26.9 g, 344 mmol, 3 equiv) in DCM (150 mL) was
added dropwise. After the reaction was stirred at ꢁ78 ꢀC for 20 min,
7c (from previous step) in DCM (150 mL) was added dropwisely and
the system was stirred at ꢁ78 ꢀC for another 1 h. Triethylamine
(69.7 g, 689 mmol, 6 equiv) was added slowly. The reaction was
then warmed to rt followed by quenched with H2O (100 mL) and
extracted with ethyl acetate (150 mLꢂ3). The combined organic
extract was washed with brine and dried over Na2SO4. The organic
extract was concentrated under reduced pressure and purified by
column chromatography on silica gel to give 24.5 g of crude 8c.
A 1000 mL flask equipped with a stir bar was charged with crude
8c (from previous step), Pd(OH)2 (5.4 g, Pd 20% on carbon, nomi-
nally 50% water, Pearlman’s catalyst), HOAc (400 mL), and 6 M HCl
(80 mL). The system was quickly put under vacuum and back-filled
with H2 gas for three times. The flask was then equipped with a H2-
filled balloon and stirred at 40 ꢀC for overnight. The black reaction
mixture was directly filtered through Celite, and the filtrate was
concentrated directly under rotavapor. The residue was purified by
column chromatography on silica gel to give 11.5 g of compound 3
as a light yellow solid in 75% yield over three steps.
NMR (101 MHz, CDCl3) d 184.9 (s), 152.4 (s), 150.5 (s), 144.6 (s), 137.7
(s), 132.4 (s), 116.3 (s), 115.1 (s), 111.8 (s), 74.7 (s), 51.2 (s), 33.0 (s),
31.9 (s), 29.5 (s), 29.4 (s), 29.3 (s), 27.5 (s), 22.7 (s), 14.1 (s). IR:
n
2926.05, 2854.75, 1768.76, 1603.38, 1574.27, 1474.60, 1275.33,
1158.42, 1128.28, 1050.87, 990.80, 946.75, 898.03, 782.03,
þ
758.76 cmꢁ1. HRMS calcd for C19H26NaO2 [MþNa]þ: 309.1825,
found: 309.1824.
4.8. General procedure G: DMP oxidation II
A 10 mL flask equipped with a stir bar was charged with ben-
zocyclobutenols (0.2 mmol, 1 equiv), DMP (0.3 mmol, 1.5 equiv),
and NaHCO3 (0.3 mmol, 1.5 equiv). DCM (2 mL) was added and the
reaction was monitored by TLC. Upon disappearance of benzocy-
clobutenols, the reaction was directly purified by column chroma-
tography on silica gel to afford the following compounds.
4.8.1. 5-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)bicyclo[4.2.0]octa-
1,3,5-trien-7-one (8g). Compound 8g was obtained in 85% yield as
a white solid (40 mg) from 7g, Rf¼0.7 (Hexane/EtOAc¼5:1); 1H
NMR (400 MHz, CDCl3)
d
7.41 (dd, J¼8.4, 7.1 Hz, 1H), 6.99 (dd, J¼7.1,
0.4 Hz, 1H), 6.82 (dd, J¼8.4, 0.4 Hz, 1H), 4.47e4.44 (m, 2H),
4.9.1. 5-Hydroxybicyclo[4.2.0]octa-1,3,5-trien-7-one
(36a). Rf¼0.2
3.96e3.93 (m, 2H), 3.89 (s, 2H), 0.86 (s, 9H), 0.05 (s, 6H). 13C NMR
(Hexane/EtOAc¼5:1); 1H NMR (400 MHz, CDCl3)
d
8.34 (s, 1H), 7.45
(101 MHz, CDCl3)
116.3 (s),114.9 (s), 73.8 (s), 62.1 (s), 51.1 (s), 25.9 (s),18.4 (s), ꢁ5.2 (s).
IR: 2955, 2927, 2857, 1766, 1604, 1574, 1471, 1442, 1277, 1253, 1137,
d
185.0 (s), 152.7 (s), 150.4 (s), 137.7 (s), 132.3 (s),
(dd, J¼8.4, 7.1 Hz, 1H), 7.02 (dd, J¼7.1, 0.5 Hz, 1H), 6.81 (dd, J¼8.4,
0.5 Hz, 1H), 3.91 (t, J¼0.7 Hz, 1H).
n
1124, 1092, 1060, 955, 946, 881, 833, 787 cmꢁ1. HRMS calcd for
Acknowledgements
C
16H24NaO3Siþ [MþNa]þ: 315.1387, found: 315.1390. Mp (ꢀC):
46e48.
We thank UT Austin and Cancer Prevention and Research In-
stitute of Texas for a startup fund, National Institute of General
Medical Sciences (R01GM109054-01) and the Welch Foundation (F
1781) for research grants. G.D. is a Searle Scholar. We thank Pro-
fessors Sessler, Siegel and Anslyn for loaning chemicals. We thank
Professor Liu for loaning lab space. We also thank Johnson Matthey
for a generous donation of Rh salts.
4.8.2. 5-(Dimethylamino)bicyclo[4.2.0]octa-1,3,5-trien-7-one
(8i). Compound 8i was obtained in 21% yield as an orange oil
(7 mg) from 7i, Rf¼0.3 (Hexane/EtOAc¼5:1); 1H NMR (400 MHz,
CDCl3)
d
7.31 (dd, J¼8.6, 6.9 Hz, 1H), 6.64 (d, J¼6.9 Hz, 1H), 6.36 (d,
J¼8.6 Hz, 1H), 3.76 (s, 2H), 3.18 (s, 6H). 13C NMR (101 MHz, CDCl3)
d
185.8 (s), 151.3 (s), 145.1 (s), 137.2 (s), 129.6 (s), 110.3 (s), 109.0 (s),
49.7 (s), 40.8 (s). IR: n 2919, 1734, 1616, 1576, 1506, 1436, 1418, 1383,
1191, 1116, 1046, 89, 766, 643 cmꢁ1. HRMS calcd for C10H12NOþ
Supplementary data
[MþH]þ: 162.0913, found: 162.0907.
NMR spectra of all new compounds are found in Supplementary
data. Supplementary data associated with this article can be found
in the online version, at http://dx.doi.org/10.1016/j.tet.2014.03.080.
4.9. Gram-scale synthesis of compound 3
To a 1000 mL flamed-dried flask equipped with a stir bar and
a nitrogen-filled balloon was added THF (250 mL). The system was
cooled to 0 ꢀC with an ice-water bath before n-BuLi (2.5 M in
hexane, 77.6 mL, 194 mmol, 1.7 equiv) was added dropwisely. Upon
completion, the system was warmed to rt and stirred for 16 h
under nitrogen atmosphere. At the same time, to a 250 mL flamed-
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