A [4+4] annulation strategy for the synthesis of eight-membered carbocycles based on intramolecular cycloadditions of conjugated enynes

Article abstract of DOI:10.1016/j.tet.2011.09.031

A [4+4] annulation strategy for the synthesis of eight-membered carbocycles is reported that proceeds via a cascade involving two pericyclic processes. In the first step, the [4+2] cycloaddition of a conjugated enyne with an electron-deficient cyclobutene

Full text of DOI:10.1016/j.tet.2011.09.031

Tetrahedron 67 (2011) 9890e9898
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A [4þ4] annulation strategy for the synthesis of eight-membered carbocycles
based on intramolecular cycloadditions of conjugated enynes
*
Julia M. Robinson, Sami F. Tlais, Jennie Fong, Rick L. Danheiser
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 August 2011
Received in revised form 8 September 2011
Accepted 9 September 2011
Available online 14 September 2011
A [4þ4] annulation strategy for the synthesis of eight-membered carbocycles is reported that proceeds
via a cascade involving two pericyclic processes. In the first step, the [4þ2] cycloaddition of a conjugated
enyne with an electron-deficient cyclobutene generates a strained six-membered cyclic allene that
isomerizes to the corresponding 1,3-cyclohexadiene. In the second step, this bicyclo[4.2.0]octa-2,4-diene
intermediate undergoes thermal or acid-promoted 6-electron electrocyclic ring opening to furnish
a 2,4,6-cyclooctatrienone. The latter transformation represents the first example of the promotion of
6-electron electrocyclic ring opening reactions by acid.
Dedicated to Professor Gilbert Stork on the
occasion of his 90th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Conjugated enynes
Eight-membered rings
Cycloaddition
Electrocyclic ring opening
Cyclooctatrienones
1. Introduction
cycloaddition of a conjugated enyne with a cyclobutene derivative
generates a cyclic allene of general type 3 that is expected to rapidly
[4þ2] Cycloadditions of conjugated enynes1,2 generate six-
membered carbocycles that incorporate an additional element of
unsaturation relative to the cycloadducts produced in conventional
DielseAlder reactions. When alkynes are employed as ‘enyno-
philes’, the cyclic allenes3 initially produced isomerize to form
benzenoid aromatic compounds (Scheme 1).4 This version of the
enyne cycloaddition provides an attractive alternative to benzan-
nulations based on DielseAlder reactions of specially designed di-
isomerize via either proton or hydrogen atom transfer pathways to
afford the bicyclo[4.2.0]-2,4-octadiene intermediate 4. Electrocyclic
ring opening9 then produces the desired eight-membered ring
containing system. In principle, the conversion of enyne cycload-
dition substrate 1 to cyclooctatriene 2 should be possible in a single
synthetic operation as a cascade (‘domino’) reaction process.10
Although the thermal interconversion of bicyclo[4.2.0]-2,4-
octadienes and 1,3,5-cyclooctatrienes is an equilibrium process
that often favors the bicyclic system, in this case we expected to be
able to direct the reaction to favor the desired eight-membered ring
isomer through the appropriate choice of substituents (vide infra).
ene substrates, such as a-pyrones. In enyne cycloadditions where
alkenes are employed as enynophiles, conjugated cyclohexadienes
are generated that potentially can undergo in situ rearrangement
leading to the formation of other useful cyclic systems. Herein we
describe the application of this latter approach in a new [4þ4]
annulation strategy for the synthesis of eight-membered carbocy-
clic compounds.
Eight-membered carbocyclic rings are key features in the
structures of several important classes of bioactive natural products
and are relatively difficult to access using conventional methodol-
ogy.5 Scheme 2 outlines our new [4þ4] annulation strategy6e8 for
the synthesis of eight-membered rings. Intramolecular [4þ2]
2. Results and discussion
2.1. [4D4] Annulation with cyclobutenones
As in the case of DielseAlder reactions and dipolar cycloaddi-
tions, the [4þ2] cycloaddition of conjugated enynes proceeds with
the greatest facility when electron-deficient
p bonds are employed
as reaction partners.1,2 We began our investigation of the proposed
[4þ4] annulation strategy by examining the cycloaddition of enyne
7 in which a cyclobutenone11 serves as the enynophile component.
Eq. 1 outlines the synthesis of cyclobutenone 7, which features the
* Corresponding author. E-mail address: danheisr@mit.edu (R.L. Danheiser).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.031

J.M. Robinson et al. / Tetrahedron 67 (2011) 9890e9898
9891
Scheme 1. [4þ2] Cycloadditions of conjugated enynes.
cyclooctatrienone 8 (30%) and indan 13 (36%). Scheme 3 outlines
a plausible mechanism for the formation of these two major
products of the reaction. The electrocyclic cleavage of bicyclo
[4.2.0]-2,4-octadienes usually requires elevated temperatures,
typically in the range 60e100 ꢀC. In many cases an equilibrium
mixture of bicyclooctadiene and cyclooctatriene is observed, with
the ratio dependent on the nature of the substituents.17 In the case
of the ketoneeLewis acid complex 9, we expected the ring opening
to proceed under unusually mild conditions and to greatly favor 10
due to the increased delocalization of positive charge in the product
of electrocyclic opening. Note that the transformation of 9 to 10 can
also be viewed as a variant of the well known cyclobutyl to
homoallyl carbocation rearrangement. In a similar fashion, the
formation of the aromatic ketone byproduct 13 could be proceeding
via cyclobutyl carbocation rearrangement involving the alternate
C2eC3 bond of the four-membered ring to generate the delocalized
pentadienyl cation intermediate 11.
Scheme 2. [4þ4] Annulation strategy for the synthesis of eight-membered
carbocycles.
reaction of 3-ethoxycyclobutenone12 with an organolithium com-
pound prepared beginning from the known enynyl alcohol 5.13,14
2 equiv t-BuLi, -78 °C
CH3
Et2O-pentane;
CH3
3-ethoxycyclobutenone;
TFAA, -78 °C, 6 h;
(1)
aq NaHCO3, rt
Z
39-42%
5: Z = OH
Ph3P, I2
imidazole, THF
0 °C, 1 h
7
O
96%
6: Z = I
Cyclobutenones undergo 4-electron electrocyclic ring opening
to form vinylketenes at elevated temperature,15 so we initially ex-
amined the [4þ2] enyne cycloaddition of 7 in the presence of Lewis
and Brønsted acids2a in the hope of achieving the desired trans-
formation at rt or below. In the event, exposure of cyclobutenone 7
to MsOH or Lewis acids, such as TiCl4, AlCl3, and Me2AlCl produced
complex mixtures, but we were pleased to find that reaction with
BF3-etherate at rt gave the desired cyclooctatrienone 816 in 35%
yield (Eq. 2).
Scheme 3. Mechanism for the formation of [4þ4] product 8 and byproduct 13.
Two other cyclobutenone cycloaddition substrates (14 and 15)
were next prepared and subjected to treatment with both Lewis and
Brønsted acids under a variety of conditions. None of the desired
[4þ4] annulation products were detected in these reactions, which
either returnedunreacted starting material orled tothe formation of
complex mixtures of uncharacterizable products. We therefore next
turned our attention to systems in which the carbonyl activating
group is positioned exocyclic with respect to the cyclobutene ring. It
was our expectation that these substrates would not be subject to
the unproductive mode of fragmentation observed in the reactions
of cyclobutenones, and might therefore undergo the desired [4þ4]
annulation more efficiently and in good yield.
CH3
CH3
1.1 equiv BF3-Et2O
CH2Cl2, rt 21 h
(2)
35%
8
O
7
O
Under these and related conditions, an aromatic ketone
byproduct was also isolated in comparable amounts that was
identified as the indan derivative 13. For example, reaction of 7
with 1.4 equiv of BF3-etherate at 50 ꢀC for 4 h afforded a mixture of

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J.M. Robinson et al. / Tetrahedron 67 (2011) 9890e9898
protocol for the [4þ2] cycloaddition involves reaction with MsOH
CH3
CH3
at ꢁ30 to ꢁ15 ꢀC.
14
15
O
O
O
2.2. [4D4] Annulation with acylcyclobutenes
Scheme 4 outlines our syntheses of acylcyclobutene cycloaddition
substrates 20e23, which are based on an application of the Weinreb
ketone synthesis.18,19 The requisite cyclobutenyl Weinreb amide
building block (19) was prepared from cyclobutenecarboxylic acid20
in 79% yield by treatment with oxalyl chloride (cat. DMF, CH2Cl2, rt,
1 h) followed by addition of 1.1 equiv of N,O-dimethylhydroxylamine
hydrochloride and 2.2 equiv of Et3N (rt, 1 h).
Scheme 5. [4þ4] Annulations of acylcyclobutenes 24 and 25.
Thermolysis of unpurified tricyclic ketone 24 at 90e95 ꢀC
overnight brought about the desired 6-electron electrocyclic
opening reaction affording the cyclooctatriene 26 in 78% overall
yield from 21 after purification by column chromatography. Sur-
prisingly, some samples of 21 underwent rearrangement upon
heating for several hours at only 70 ꢀC. We hypothesized that ad-
ventitious acid might be promoting the rearrangement in these
cases, and indeed, in the presence of added acid (camphorsulfonic
acid, CSA) complete conversion to 26 was observed to take place at
only 50 ꢀC. Rearrangement of the tricyclic ketone 25 (with R¼H)
was slower, and in this case even at 100 ꢀC no reaction was ob-
served in the absence of acid, although the desired rearrangement
did occur smoothly in the presence of 2 equiv of CSA.
The critical role of acid in promoting the rearrangement of 24
and 25 to 26 and 27 was confirmed by the observation that reaction
is inhibited in the presence of an acid scavenger. For example, no
electrocyclic ring opening was observed when the bicyclooctadiene
intermediate 25 was heated overnight at 100 ꢀC in the presence of
calcium carbonate, and the tricyclic ketone was recovered in 83%
yield after column chromatography. We attribute the acceleration
of the electrocyclic ring opening of intermediates of type 28 relative
to the unprotonated ketones to the fact that significant de-
localization of positive charge develops in the transition state
leading to the eight-membered ring products 29 (Eq. 3). To our
knowledge, these transformations represent the first examples of
the acceleration of a 6-electrocyclic ring opening reaction by acid.
Note, however, that Bergman and Trauner have recently reported
the acceleration of 6-electron electrocyclic ring closure reactions of
hexatrienes by catalytic amounts of Me2AlCl.22
Scheme 4. Synthesis of acylcyclobutene cycloaddition substrates.
The [4þ4] annulation with acylcyclobutene 21 was examined
first. No reaction of this substrate was observed upon heating at
110 ꢀC, while at higher temperatures the desired cyclooctatriene 26
was observed to form, but only as one component in a complex
mixture of products. In the presence of BF3-etherate only a small
amount of 26 was detected upon reaction at ꢁ55 ꢀC, and at higher
temperatures significant polymerization took place. However, ex-
posure of cyclobutenyl ketone 21 to 1 equiv of MsOH at ꢁ78 ꢀC led
to a relatively clean reaction to afford the desired intermediate
tricyclic ketone 24. This compound could not be purified without
partial decomposition, and therefore was best carried on in the
electrocyclic ring opening step without prior purification.
In some trials the treatment of 21 with MsOH at ꢁ78 ꢀC led to
incomplete cycloaddition, and reaction at higher temperature
resulted in the formation of numerous byproducts. After some
experimentation, a more reproducible protocol was developed
utilizing reaction with 2,4,6-triisopropylbenzenesulfonic acid
(‘TIPPSO3H’)21 at 0 ꢀC. Thus, exposure of 21 to the action of 0.5 equiv
of TIPPSO3H in dichloromethane at 0 ꢀC for 2 h cleanly furnished
the desired tricyclic ketone 24 in good yield (Scheme 5). Other
acids, such as TsOH, camphorsulfonic acid, and trifluoroacetic acid
were not effective promoters of the enyne cycloaddition and led to
either sluggish reaction, or decomposition at higher temperatures.
Interestingly, the related enyne substrate 20 was found to react
slowly in the presence of TIPPSO3H, and in this case the optimal
R
R
(3)
O
H
O
28
29
H
Efficient [4þ4] annulation did not take place in the case of
several related acylcyclobutenes, including enyne 3023 (with
a three-atom rather than four-atom ‘tether’24) and the ester de-
rivatives 31 and 3225 (Eq. 4). In each case, no reaction was observed

J.M. Robinson et al. / Tetrahedron 67 (2011) 9890e9898
9893
in the presence of acid at rt or below, and complex mixtures of
products were formed at elevated temperatures.
that undergo acid-promoted electrocyclic ring opening under mild
conditions to afford the desired cyclooctatrienones. These trans-
formations represent the first examples of the application of acid to
promote a 6-electron electrocyclic ring opening reaction.
CH3
CH3
4. Experimental
(4)
Z
Z
4.1. General procedures
O
O
All reactions were performed in flame-dried or oven-dried
glassware under a positive pressure of argon. Reaction mixtures
were stirred magnetically unless otherwise indicated. Air- and
moisture-sensitive liquids and solutions were transferred by sy-
ringe or cannula and introduced into reaction vessels through
rubber septa. Reaction product solutions and chromatography
fractions were concentrated by rotary evaporation at ca. 20 mmHg
and then at 0.1 mmHg (vacuum pump) unless otherwise indicated.
Thin layer chromatography was performed on EMD precoated
glass-backed silica gel 60 F254 0.25 mm plates.
30: Z = CH2
31: Z = O
33: Z = CH2
34: Z = O
32: Z = OCH2
35: Z = OCH2
Finally, successful [4þ4] annulation was achieved with acylcy-
clobutenes 22 and 23, providing access to the tricyclic eight-
membered ring containing products 38 and 39 (Scheme 6). In the
case of the [4þ2] cycloaddition of enyne 22, reaction with MsOH
generated the desired cyclohexadiene intermediate 36 accompa-
nied by a significant amount of an isomeric diene 40.
4.2. Materials
Commercial grade reagents and solvents were used without fur-
ther purification except as indicated below. Dichloromethane, diethyl
ether, and tetrahydrofuran were purified by pressure filtration
through activated alumina. CuI was purified by Soxhlet extraction
with THF for 48 h followed by drying under vacuum (0.1 mmHg) over
P2O5 for 24 h. Diisopropylamine, triethylamine, pentane, and boron
trifluoride etherate were distilled under argon from calcium hydride.
TFAA was distilled under argon. 2-Bromopropene was filtered
through activated basic alumina before use. n-Butyllithium was ti-
trated accordingtothe methodofWatsoneEastham using BHT inTHF
with 1,10-phenanthroline as an indicator.26 tert-Butyllithium was ti-
trated in pentane with menthol at 0 ꢀC using 1,10-phenanthroline as
the indicator. 3-Ethoxycyclobutanone,12 cyclobutenecarboxylic
acid,20 cyclopentenyl trifluoromethanesulfonate,27 and 2,4,6-tri(iso-
propyl)benzenesulfonic acid (TIPPSO3H)21 were prepared according
to the previously reported procedures. Cyclohexenyl tri-
fluoromethanesulfonatewaspreparedviaaminormodificationofthe
published procedure28 in which LiHMDS was substituted for LDA.
Column chromatography was performed on Sorbent Technologies
Standard Grade silica gel 60 (230e400 mesh) or on EMD Chromato-
graphic Grade basic alumina (80e325 mesh). Chromatography with
acetone-deactivatedsilicagelwascarriedoutbymixingsilicagelwith
acetone (ca. 10 mL/g) for 5 min, using this slurry to build a column,
and then flushing the column with two column volumes of hexanes
before applying the sample to be purified.
Scheme 6. [4þ4] Annulations of acylcyclobutenes 38 and 39.
O
40
Formation of the isomeric diene 40 could arise via the pathway
outlined in Eq. 5. Under the acid-promoted enyne cycloaddition
conditions, isomerization of the intermediate cyclic allene 41 pro-
ceeds via protonation to form an allylic carbocation of type 42. In
this case, proton loss apparently produces 40 in addition to the
desired endocyclic diene 36, possibly due to increased ring strain in
this tetracyclic system. An analogous isomeric diene byproduct was
also observed to form in the cycloaddition of the cyclohexenyl
substrate 23.
4.3. Instrumentation
Infrared spectra were obtained using a PerkineElmer 2000 FT-IR
spectrophotometer. 1H NMR spectra were recorded on a Bruker
Avance-400 (400 MHz) spectrometer. 1H NMR chemical shifts are
H
36
expressed in parts per million (d) downfield from tetramethylsilane
(5)
(with the CHCl3 peak at 7.27 ppm used as a standard). 13C NMR
spectra were recorded on a Bruker Avance-400 (100 MHz) spec-
trometer. 13C NMR chemical shifts are expressed in parts per million
22
40
O
O
41
42
(d) downfield from tetramethylsilane (with the central peak of
CHCl3 at 77.23 ppm used as a standard). High-resolution mass
spectra (HRMS) were measured on a Bruker Daltonics APEXII 3 T
Fourier transform mass spectrometer.
3. Conclusions
A [4þ4] annulation strategy for the construction of eight-
membered carbocycles has been developed that involves a new
variant of the enyne [4þ2] cycloaddition in which cyclobutenones
4.4. Synthesis of cycloaddition substrates
and acylcyclobutenes serve as the 2
p
‘enynophile’ reaction part-
4.4.1. General procedure for conversion of alcohols to iodides: 7-iodo-
ners. The [4þ2] cycloaddition products are bicyclo[4.2.0]octadienes
2-methylhept-1-en-3-yne (6). A 50-mL, three-necked, round-

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J.M. Robinson et al. / Tetrahedron 67 (2011) 9890e9898
bottomed flask equipped with a stir bar, rubber septum, glass
stopper, and argon inlet adapter was charged with the alcohol 5
(0.759 g, 6.12 mmol, 1.0 equiv) and 10 mL of THF. The solution was
cooled to 0 ꢀC, and triphenylphosphine (1.60 g, 6.12 mmol,
1.0 equiv), imidazole (0.624 g, 9.16 mmol, 1.5 equiv), and iodine
(2.31 g, 9.10 mmol, 1.5 equiv) were each added in one portion. The
reaction mixture became dark brown in color. The solution was
stirred at 0 ꢀC in the dark for 2.5 h, and then diluted with 100 mL of
satd aq Na2S2O3 solution and extracted with five 50-mL portions of
pentane. The combined organic layers were washed with 50 mL of
brine, dried over MgSO4, filtered, and concentrated at 0 ꢀC
(20 mmHg). The colorless oil containing some white solid was fil-
tered through a short plug of activated basic alumina using 80 mL of
pentane and the filtrate was concentrated at 0 ꢀC (20 mmHg) to
give 1.369 g (96%) of iodide 6 as a colorless oil: IR (neat) 3094, 2950,
concentrated at 0 ꢀC (20 mmHg) to provide 2.38 g of a brown oil.
Column chromatography on 54 g of silica gel (elution with 15e40%
Et2Oepentane) gave 1.77 g (81%) of alcohol 17a as a goldenyellow oil:
IR (neat) 3334, 2949, 2227,1841,1609,1433,1061, 975, and 920 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
5.78 (ddt, J¼17.5, 11.0, 2.1 Hz, 1H), 5.57
(ddd, J¼17.5, 2.2, 0.5 Hz,1H), 5.41 (ddd, J¼11.0, 2.2, 0.4 Hz,1H), 3.78 (q,
J¼5.9 Hz, 2H), 2.45 (td, J¼6.9, 2.1 Hz, 2H), 1.80 (quint, J¼6.5 Hz, 2H),
1.43e1.51 (m,1H);13C NMR (100 MHz,CDCl3)
d 126.0,117.5, 90.3, 79.9,
61.6, 31.4, 15.9; HRMS-ESI (m/z) [MþH]þ calcd for C7H10O: 111.0810,
found: 111.0805.
4.4.4. 5-(Cyclopent-1-en-1-yl)pent-4-yn-1-ol (17b). A 100-mL,
three-necked, round-bottomed flask equipped with an argon inlet
adapter and two rubber septa was charged with PdCl2(PPh3)2
(0.069 g, 0.10 mmol, 0.02 equiv), CuI (0.038 g, 0.20 mmol,
0.04 equiv), and 10.5 mL of diisopropylamine. The orange reaction
mixture was stirred at rt while a solution of cyclopentenyl tri-
fluoromethanesulfonate (1.4 g, 6.5 mmol, 1.3 equiv) in 10 mL of THF
was added dropwise via cannula over 2 min (1.8-mL THF rinse). The
reaction mixture was stirred for 5 min, and then a solution of 4-
pentyn-1-ol (0.46 mL, 0.42 g, 5.0 mmol, 1.0 equiv) in 20 mL of THF
was added dropwise via cannula over 27 min. The reaction mixture
was stirred at rt for 1 h, 10 mL of H2O was added, and the resulting
mixture was extracted with two 75-mL portions of Et2O. The
combined organic phases were washed with 25 mL of brine, dried
over MgSO4, filtered, and concentrated to give 1.5 g of orange oil.
Purification by column chromatography on 91 g of silica gel (elution
with 5e35% EtOAcehexanes) afforded 0.654 g (88%) of alcohol 17b
as a red oil: IR (neat) 3332, 2950, 2223, 1611, 1440, 1326, 1057, 950,
2919, 2229, 1796, 1614, 1427, 1221, and 895 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
5.21e5.24 (m, 1H), 5.17 (app quint, J¼1.6 Hz,
1H), 3.32 (t, J¼6.8 Hz, 2H), 2.46 (t, J¼6.7 Hz, 2H), 2.03 (quint,
J¼6.8 Hz, 2H), 1.88 (dd, J¼1.5, 1.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 127.2, 121.1, 87.0, 83.1, 32.4, 24.0, 20.5, 5.6; HRMS-ESI (m/z)
[M]þ calcd for C8H11I: 233.9900, found: 233.9904.
4.4.2. 3-(6-Methylhept-6-en-4-ynyl)cyclobut-2-enone (7). A 100-
mL, three-necked, round-bottomed flask equipped with a stir bar,
rubber septum, thermocouple probe, argon inlet adapter, and 25-mL
addition funnel fitted with a rubber septum was charged with the
iodide 6 (1.20 g, 5.14 mmol, 1.3 equiv), 4.5 mL of pentane, and
11.4 mL of Et2O. The solution was cooled at ꢁ78 ꢀC while t-BuLi so-
lution (1.63 M solution in pentane, 6.34 mL, 10.3 mmol, 2.7 equiv)
was added dropwise via the addition funnel over 15 min. The
resulting mixture was stirred at ꢁ78 ꢀC for 5 min, and then a solu-
tion of 3-ethoxycyclobutenone12 (0.428 g, 3.81 mmol, 1.0 equiv) in
3 mL of Et2O was added dropwise via cannula over 3 min (2-mL Et2O
rinse). The reaction mixture became dark orange. After 1 h, TFAA
(0.92 mL,1.4 g, 6.6 mmol,1.7 equiv) was added dropwise via syringe
over 30 s. The reaction mixture was stirred at ꢁ78 ꢀC for 6 h, and
then 11 mL of satd aq NaHCO3 solution was added dropwise via
syringe over 5 min. The resulting mixture was allowed to warm to rt
over 20 min and then diluted with 40 mL of Et2O. The aqueous layer
was separated and extracted with three 20-mL portions of Et2O, and
the combined organic layers werewashed with 30 mL of brine, dried
over MgSO4, filtered, and concentrated at 5 ꢀC (20 mmHg) to give
1.314 g of a red brown oil. Column chromatography on 255 g of silica
gel (elution with 15e30% Et2Oepentane) afforded 0.259 g (39%) of
cyclobutenone 7 as a yellow-orange oil: IR (neat) 2223, 1767, 1614,
1585, 1452, 1434, 1415, 1051, 1021, 897, 860, and 840 cmꢁ1; 1H NMR
and 809 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 5.93e5.98 (m, 1H), 3.78
(q, J¼5.9 Hz, 2H), 2.47 (t, J¼7.0 Hz, 2H), 2.36e2.45 (m, 4H), 1.89
(quint, J¼7.6 Hz, 2H), 1.80 (quint, J¼6.2 Hz, 2H), 1.52 (t, J¼5.4 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 136.6, 124.8, 90.6, 78.6, 62.0, 36.7,
33.2, 31.6, 23.4, 16.2; HRMS-ESI (m/z) calcd for C10H14O [MþH]þ:
151.1117, found: 151.1113.
4.4.5. 5-(Cyclohex-1-en-1-yl)pent-4-yn-1-ol (17c). A 100-mL, three-
necked, round-bottomed flask equipped with an argon inlet adapter
and two rubber septa was charged with PdCl2(PPh3)2 (0.077 g,
0.11 mmol, 0.020 equiv), CuI (0.04 g, 0.22 mmol, 0.04 equiv), and i-
Pr2NH(11.5 mL, 8.30 g, 82 mmol,15 equiv). Asolutionofcyclohexenyl
trifluoromethanesulfonate (1.64 g, 7.12 mmol, 1.3 equiv) in 11 mL of
THF was added dropwise over 2 min (2-mL THF rinse), and then
a solution of 4-pentyn-1-ol (0.51 mL, 0.46 g, 5.5 mmol, 1.0 equiv) in
20 mL of THF was added dropwise over 22 min. The reaction mixture
wasstirred atrtfor1 h, and then 75 mLofEt2O and 10 mLofH2O were
added. The organic phase was separated and washed with 10 mL of
H2O and 25 mL of brine, dried over MgSO4, filtered, and concentrated
to give 2.54 g of red oil. Purification by column chromatography on
152 g of silica gel (elution with 5e30% EtOAcehexanes) afforded
0.830 g (92%) of alcohol 17c as a dark red oil: IR (neat) 3334, 2930,
(400 MHz, CDCl3)
1H), 3.20 (s, 2H), 2.71 (td, J¼7.6, 1.2 Hz, 2H), 2.43 (t, J¼6.9 Hz, 2H),
1.83e1.92 (m 5H); 13C NMR (100 MHz, CDCl3)
188.0, 180.3, 134.7,
d
5.95 (s, 1H), 5.21e5.24 (m, 1H), 5.18 (t, J¼1.7 Hz,
d
127.1, 121.1, 87.6, 83.1, 51.0, 31.3, 25.3, 23.9, 19.1; HRMS-ESI (m/z)
[MþNa]þ calcd for C12H14O: 197.0937, found: 197.0938.
2220, 1631, 1435, 1347, 1136, 1052, 918, 842, 801, and 730 cmꢁ1
NMR (400 MHz, CDCl3)
5.99e6.05 (m, 1H), 3.78 (q, J¼5.8 Hz, 2H),
2.43 (t, J¼6.9 Hz, 2H), 2.02e2.16 (m, 4H), 1.79 (quint, J¼6.3 Hz, 2H),
1,52e1.66 (m, 5H); 13C NMR (100 MHz, CDCl3)
133.8, 121.0, 86.5,
;
1H
4.4.3. Hept-6-en-4-yn-1-ol (17a). A 100-mL, three-necked, round-
bottomed flask equipped with a stir bar, argon inlet adapter, two
rubber septa, and thermocouple probe was charged with
PdCl2(PPh3)2 (0.281 g, 0.401 mmol, 0.02 equiv), CuI (0.152 g,
0.797 mmol, 0.04 equiv), and Et3N (4.2 mL, 3.0 g, 30 mmol,1.5 equiv).
The orange reaction mixture was cooled to 0 ꢀC and vinyl bromide
(40 mL of a 1.0 M solution in THF, 40 mmol, 2.0 equiv) was added in
one portion. A solution of 4-pentyn-1-ol (1.86 mL, 1.68 g, 20.0 mmol,
1.0 equiv) in 2.8 mL of THF was added dropwise via cannula over
20 min (1.4-mL THF rinse), and the dark brown reaction mixture was
allowed to warm to rt over 30 min. After 1.5 h, the reaction mixture
was filtered through a plugof 2 g of silica gel with the aid of 300 mL of
Et2O. The filtrate was washed with two 100-mL portions of satd aq
NaHCO3 solution and 100 mL of brine, dried over MgSO4, filtered, and
d
d
83.2, 62.2, 31.7, 29.7, 25.7, 22.5, 21.7, 16.1; HRMS-DART (m/z) calcd for
C11H16O [MþH]þ: 165.1274, found: 165.1279.
4.4.6. 7-Iodohept-1-en-3-yne (18a). Reaction of alcohol 17a
(0.865 g, 7.85 mmol, 1.0 equiv) with imidazole (0.801 g, 11.8 mmol,
1.5 equiv), triphenylphosphine (2.06 g, 7.85 mmol, 1.0 equiv), and
iodine (3.010 g, 11.86 mmol, 1.5 equiv) in 13 mL of THF for 1 h
according to the general procedure afforded a colorless oil con-
taining some white solid. This material was filtered through a short
plug of basic alumina using 50 mL of pentane and the filtrate was
concentrated at 0 ꢀC (20 mmHg) to afford 1.625 g (94%) of iodide

J.M. Robinson et al. / Tetrahedron 67 (2011) 9890e9898
9895
18a as a colorless oil containing some white solid: IR (neat) 3097,
3007, 2938, 2905, 2837, 2227, 1841, 1608, 1427, 1220, 1169, 973, and
round-bottomed flask equipped with an argon inlet adapter, two
rubber septa, and a thermocouple probe was charged with iodide
18a (1.163 g, 3.58 mmol,1.1 equiv) and 10.4 mL of Et2O. The reaction
mixture was cooled to ꢁ78 ꢀC and t-BuLi solution (1.70 M in pen-
tane, 4.25 mL, 7.22 mmol, 2.3 equiv) was added dropwise over
9 min. The bright yellow reaction mixture was stirred at ꢁ78 ꢀC for
20 min, and then a solution of Weinreb amide 19 (0.440 g,
3.12 mmol, 1.0 equiv) in 5.2 mL of THF29 was added dropwise over
8 min. The reaction mixture was stirred at ꢁ78 ꢀC for 1 h, and then
20 mL of satd aq NH4Cl solution was added dropwise over 5 min.
The reaction mixture was allowed to warm to 0 ꢀC over 10 min and
then diluted with 100 mL of Et2O and 25 mL of satd aq NH4Cl so-
lution. The aqueous phase was separated and extracted with two
50-mL portions of Et2O. The combined organic phases were washed
with 50 mL of brine, dried over MgSO4, filtered, and concentrated
(5e10 ꢀC, 20 mmHg) to give 1.04 g of yellow oil. Purification by
column chromatography on 115 g of acetone-deactivated silica gel
(elution with 0e5% EtOAcehexanes) provided 0.300 g (55%) of
enone 20 as a pale yellow oil: IR (neat) 2226, 1671, 1589, 1435, 1372,
1334, 1231, 1190, 1073, 1000, 975, 917, 855, and 730 cmꢁ1; 1H NMR
919 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
5.78 (ddt, J¼17.5,11.0, 2.1 Hz,
1H), 5.58 (ddt, J¼17.5, 2.2, 0.6 Hz, 1H), 5.42 (dd, J¼11.0, 1.1 Hz, 1H),
3.32 (t, J¼6.8 Hz, 2H), 2.47 (td, J¼6.7, 2.1 Hz, 2H), 2.03 (quint,
J¼6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 126.4, 117.5, 88.8, 80.6,
32.3, 20.6, 5.6; HRMS-ESI (m/z) calcd for C7H9I [MþH]þ: 220.9827,
found: 220.9825.
4.4.7. 1-(5-Iodopent-1-ynyl)cyclopent-1-ene (18b). Reaction of al-
cohol 17c (0.654 g, 4.35 mmol, 1.0 equiv) with triphenylphosphine
(1.142 g, 4.35 mmol, 1.0 equiv), imidazole (0.452 g, 6.64 mmol,
1.5 equiv), and iodine (1.401 g, 5.52 mmol,1.3 equiv) in 8.6 mL of THF
for 1.5 h according to the general procedure afforded a yellow oil
containing some white solid. Purification bycolumn chromatography
on 16 g of silica gel (elution with pentane) furnished 0.927 g (82%) of
iodide 18b as a very pale yellow oil: IR (neat) 2954, 2844, 2221, 1611,
1441, 1427, 1347, 1220, 1167, 949, and 809 cmꢁ1; 1H NMR (400 MHz,
CDCl3)
d
5.95e5.99 (m, 1H), 3.32 (t, J¼6.8 Hz, 2H), 2.48 (t, J¼6.7 Hz,
2H), 2.37e2.45 (m, 4H), 2.13 (quint, J¼6.8 Hz, 2H), 1.89 (quint,
J¼7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
136.8, 124.8, 89.0, 79.1,
(400 MHz, CDCl3)
d
6.76 (s, 1H), 5.76 (dt, J¼17.5, 11.0, 2.1 Hz, 1H),
36.7, 33.2, 32.4, 23.4, 20.7, 5.6; HRMS-ESI (m/z) calcd for C10H13
I
5.54 (dd, J¼17.5, 2.1 Hz, 1H), 5.38 (dd, J¼11.0, 2.1 Hz, 1H), 2.64e2.73
(m, 4H), 2.46e2.51 (m, 2H), 2.36 (td, J¼6.8, 1.7 Hz, 2H), 1.84 (quint,
[MþH]þ: 261.0135, found: 261.0144.
J¼7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 196.1, 147.2, 145.1, 125.9,
4.4.8. 1-(5-Iodopent-1-ynyl)cyclohex-1-ene (18c). Reaction of alco-
hol 17d (0.825 g, 5.02 mmol, 1.0 equiv) with imidazole (0.513 g,
7.53 mmol, 1.5 equiv), triphenylphosphine (1.318 g, 5.02 mmol,
1.0 equiv), and iodine (1.912 g, 7.53 mmol,1.5 equiv) in 8.4 mL for 1 h
according to the general procedure afforded a pale yellow oil. This
material was filtered through a plug of 7 g of basic alumina with the
aid of 75 mL of pentane. The filtrate was concentrated to afford
1.221 g (89%) of iodide 18c as a pale yellow oil: IR (neat) 3024, 2857,
2221, 1631, 1434, 1346, 1267, 1220, 1166, 1150, 1076, 1048, 916, 842,
117.6, 90.2, 80.2, 36.2, 28.1, 26.7, 23.1, 19.0; HRMS-ESI (m/z) [MþH]þ
calcd for C12H14O: 175.1117, found: 175.1126.
4.4.11. 1-Cyclobutenyl-7-methyloct-7-en-5-yn-1-one (21). Reaction
of iodide 6 (0.443 g, 1.89 mmol, 1.2 equiv) with t-BuLi solution
(1.47 M in pentane, 2.57 mL, 3.78 mmol, 2.4 equiv) and then with
Weinreb amide 19 (0.224 g, 1.59 mmol, 1.0 equiv) according to the
general procedure gave 0.456 g of pale yellow oil. Purification by
column chromatography on 46 g of acetone-deactivated silica gel
(elution with 0e7% EtOAcehexanes) afforded 0.150 g (50%) of
enone 21 as a yellow oil: IR (neat) 2224, 1709, 1672, 1614, 1598,
800, and 725 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.00e6.06 (s, 1H),
3.31 (t, J¼6.8 Hz, 2H), 2.44 (t, J¼6.7 Hz, 2H), 2.04e2.13 (m, 4H), 2.01
(quint, J¼6.8 Hz, 2H), 1.53e1.67 (m, 4H); 13C NMR (100 MHz, CDCl3)
1434, 1372, and 895 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.78 (t,
d
134.0, 121.0, 85.0, 83.7, 32.6, 29.7, 25.7, 22.5, 21.7, 20.5, 5.7; HRMS-
J¼1.3 Hz, 1H), 5.19e5.22 (m, 2H), 5.14e5.17 (m, 1H), 2.69e2.71 (m,
2H), 2.70 (t, J¼7.3 Hz, 2H), 2.48e2.51 (m, 2H), 2.37 (t, J¼6.9 Hz, 2H),
1.87 (dd, J¼1.5, 1.0 Hz, 3H), 1.85 (quint, J¼7.0 Hz, 2H); 13C NMR
DART (m/z) calcd for C11H15I [MþH]þ: 275.0291, found: 275.0295.
4.4.9. N-Methoxy-N-methylcyclobut-1-enecarboxamide (19). A 250-
mL, three-necked, round-bottomed flask equipped with an argon
inlet adapter and two rubber septa was charged with cyclo-
butenecarboxylic acid20 (1.13 g, 11.5 mmol, 1.0 equiv) and 70 mL of
CH2Cl2. Oxalyl chloride (1.02 mL, 1.53 g, 12.0 mmol, 1.0 equiv) and
DMF (4 drops) were added, and the resulting mixture was stirred at rt
for 1 h (gas evolution) and then cooled to 0 ꢀC. A solution of N,O-
dimethylhydroxylamine hydrochloride (1.23 g, 12.6 mmol, 1.1 equiv)
and triethylamine (3.52 mL, 2.56 g, 25.3 mmol, 2.2 equiv) in 40 mL of
CH2Cl2 was added dropwise via cannula over 5 min (5-mL CH2Cl2
rinse). The pale yellow reaction mixture was allowed to warm to rt
and stirred for 1 h in the dark. Water (50 mL) was added and the
aqueous layer was separated, neutralized with satd aq NaHCO3 so-
lution, and then extracted with two 125-mL portions of Et2O. The
combined organic layers were washed with 100 mL of brine, dried
over MgSO4, filtered, and concentrated to give 1.748 g of yellow oil.
Purification by column chromatography on 52 g of silica gel (elution
with 25e35% EtOAcehexanes) afforded 1.282 g (79%) of Weinreb
amide 19 as a very pale yellow oil: IR (neat) 2968, 2936, 1643, 1589,
(100 MHz, CDCl3) d 196.3, 147.3, 145.2, 127.3, 120.8, 88.5, 82.8, 36.3,
28.2, 26.8, 24.0, 23.3, 19.0; HRMS-ESI (m/z) [MþH]þ calcd for
C13H16O: 211.1093, found: 211.1088.
4.4.12. 1-Cyclobutenyl-6-(cyclopent-1-en-1-yl)-hex-5-yn-1-one
(22). Reaction of iodide 18b (0.898 g, 3.45 mmol, 1.15 equiv) with t-
BuLi solution (1.39 M in pentane, 5.00 mL, 6.95 mmol, 2.3 equiv)
and then with Weinreb amide 19 (0.423 g, 3.00 mmol, 1.0 equiv)
according to the general procedure gave 0.766 g of yellow oil. Pu-
rification by column chromatography on 115 g of acetone-
deactivated silica gel (elution with 0e5% EtOAcehexanes) affor-
ded 0.410 g (64%) of enone 22 as a white solid, mp 30e32 ꢀC: IR
(thin film) 2932, 1671, 1589, 1441, 1373, 1231, 1071, and 949 cmꢁ1
1H NMR (400 MHz, CDCl3)
6.74e6.79 (m, 1H), 5.91e5.98 (m, 1H),
2.67e2.74 (m, 4H), 2.48e2.52 (m, 2H), 2.36e2.46 (m, 6H),1.82e1.93
(m, 4H); 13C NMR (100 MHz, CDCl3)
196.2, 147.2, 145.1, 136.4,
;
d
d
124.9, 90.5, 78.8, 36.7, 36.3, 33.2, 28.1, 26.7, 23.4, 23.3, 19.2; HRMS-
ESI (m/z) calcd for C15H18O [MþH]þ: 215.1430, found: 215.1427.
1416, 1382, and 992 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
6.66 (t,
4.4.13. 1-Cyclobutenyl-6-(cyclohex-1-en-1-yl)-hex-5-yn-1-one
(23). Reaction of iodide 18c (1.161 g, 4.23 mmol, 1.1 equiv) with t-
BuLi solution (1.32 M in pentane, 6.45 mL, 8.51 mmol, 2.3 equiv)
and then with Weinreb amide 19 (0.522 g, 3.70 mmol, 1.0 equiv)
according to the general procedure gave 1.281 g of yellow oil. Pu-
rification by column chromatography on 152 g of acetone-
deactivated silica gel (elution with 0e4% EtOAcehexanes) affor-
ded 0.469 g (56%) of enone 23 as a colorless oil: IR (neat) 2222,
J¼1.2 Hz, 1H), 3.70 (s, 3H), 3.23 (s, 3H), 2.79e2.83 (m, 2H), 2.48 (td,
J¼3.3, 1.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 163.0, 144.9, 139.6,
61.6, 32.7, 30.7, 27.8; HRMS-ESI (m/z) [MþH]þ calcd for C7H11NO2:
142.0863, found: 142.0869.
4.4.10. General procedure for the synthesis of cyclobutenyl ketones:
1-cyclobutenylyloct-7-en-5-yn-1-one (20). A 50-mL, three-necked,

9896
J.M. Robinson et al. / Tetrahedron 67 (2011) 9890e9898
1672, 1589, 1436, 1371, 1346, 1231, 1190, 1075, 996, 918, 843, 800,
and 734 cmꢁ1; 1H NMR (400 MHz, CDCl3)
6.76 (s, 1H), 5.89e6.03
(dt, J¼13.3, 2.2 Hz, 1H), 2.54 (t, J¼6.0 Hz, 2H), 2.43 (t, J¼6.6 Hz, 2H),
2.32e2.38 (m, 2H), 2.30 (t, J¼5.9 Hz, 2H), 1.97 (quint, J¼5.5 Hz, 2H),
d
(m, 1H), 2.66e2.72 (m, 4H), 2.47e2.51 (m, 2H), 2.35 (t, J¼6.9 Hz,
1.95 (d, J¼1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 199.2, 155.8,
2H), 2.12e2.22 (m, 4H), 1.83 (quint, J¼7.0 Hz, 2H), 1.53e1.66 (m,
138.0, 136.9, 132.7, 127.6, 125.4, 38.1, 36.8, 30.6, 26.2, 23.8, 23.0;
HRMS-ESI (m/z) calcd for C13H16O [MþH]þ: 189.1279, found:
189.1277.
4H); 13C NMR (400 MHz, CDCl3)
d 196.4, 147.3, 145.0, 133.6, 121.1,
86.5, 83.4, 36.4, 29.8, 28.1, 26.7, 25.7, 23.5, 22.6, 21.8,19.0; HRMS-ESI
(m/z) [MþH]þ calcd for C16H20O: 229.1587, found: 229.1577.
Method B: A 250-mL, three-necked, round-bottomed flask
equipped with an argon inlet adapter, two rubber septa, and
a thermocouple probe was charged with enone 21 (0.136 g,
0.722 mmol, 1.0 equiv) and 72 mL of CH2Cl2. The reaction mixture
was cooled to 0 ꢀC and 2,4,6-triisopropylbenzenesulfonic acid
(0.103 g, 0.362 mmol, 0.5 equiv) was added in one portion. The
reaction mixture was stirred at 0 ꢀC for 2 h during which time the
color changed from colorless to purple. Satd aq NaHCO3 solution
(70 mL) was added in one portion and the organic phase was
separated and washed with 50 mL of brine, dried over Na2SO4,
filtered, and concentrated at 5e10 ꢀC (20 mmHg). The resulting
yellow oil was diluted with 75 mL of CH2Cl2 and transferred to
a threaded Pyrex tube (28 mm I.D., 35 mm O.D., 20-cm long)
equipped with a stir bar, rubber septum, and an argon inlet needle.
The solution was deoxygenated with a stream of argon for 5 min
and then sealed with a threaded Teflon cap. The reaction mixture
was heated at 90e95 ꢀC for 20 h and then cooled to rt and con-
centrated at 5e10 ꢀC (20 mmHg) to give a brown oil. Purification by
column chromatography on 12 g of silica gel (elution with 5%
Et2Oepentane) afforded 0.106 g (78%) of cyclooctatriene 26 as
a yellow oil.
Method C: A 250-mL, three-necked, round-bottomed flask
equipped with an argon inlet adapter, two rubber septa, and
a thermocouple probe was charged with enone 21 (0.160 g,
0.850 mmol, 1.0 equiv) and 72 mL of CH2Cl2. The reaction mixture
was cooled to 0 ꢀC and 2,4,6-triisopropylbenzenesulfonic acid
(0.120 g, 0.422 mmol, 0.5 equiv) was added in one portion. The
reaction mixture was stirred at 0 ꢀC for 2 h during which time the
color changed from colorless to purple. Satd aq NaHCO3 solution
(100 mL) was added in one portion and the organic phase was
separated, washed with 100 mL of satd aq NaHCO3 solution, dried
over Na2SO4, filtered, and concentrated at 5e10 ꢀC (20 mmHg). The
resulting yellow oil was diluted with 70 mL of CH2Cl2 and trans-
ferred to a threaded Pyrex tube (28 mm I.D., 35 mm O.D., 15-cm
long) equipped with a stir bar, rubber septum, and an argon inlet
needle. Camphorsulfonic acid (0.400 g, 1.72 mmol, 2.0 equiv) was
added and the solution was deoxygenated with a stream of argon
for 5 min. The tube was sealed with a threaded Teflon cap, heated at
50 ꢀC for 17 h, and then cooled to rt and concentrated at 5e10 ꢀC
(20 mmHg) to give a brown oil. Purification by column chroma-
tography on 12 g of silica gel (elution with 5% Et2Oepentane)
afforded 0.098 g (61%) of cyclooctatriene 26 as a yellow oil.
4.5. [4D4] Annulation with cyclobutenones
4.5.1. (6Z,8Z)-8-Methyl-2,3-dihydro-1H-cyclopenta[8]annulen-
5(4H)-one (8). A threaded Pyrex tube (35 mm O.D., 30 mm I.D., 15-
cm long) equipped with a stir bar, rubber septum, and argon inlet
needle was charged with cyclobutenone 7 (0.206 g, 1.18 mmol,
1.0 equiv), BHT (0.261 g, 1.18 mmol, 1.0 equiv), and 24 mL of CH2Cl2.
The pale yellow solution was cooled to 0 ꢀC and BF3-etherate
(0.20 mL, 0.23 g, 1.6 mmol, 1.4 equiv) was added dropwise via sy-
ringe over 30 s. The reaction mixture was stirred at 0 ꢀC for 20 min
while the color changed to orange and then tan. The rubber septum
was replaced with a Teflon cap, and the reaction mixture was
heated at 50 ꢀC. After 4 h, the solution was cooled to rt and the
Teflon cap was replaced with a rubber septum and argon inlet
needle. The reaction mixture was cooled to 0 ꢀC and 3 mL of satd aq
NaHCO3 solution was added dropwise via syringe over 1 min. The
resulting mixture was extracted with two 20-mL portions of CH2Cl2
and the combined organic layers were washed with 20 mL of brine,
dried over MgSO4, filtered, and concentrated at 10 ꢀC (20 mmHg) to
give 0.478 g of a brown oil. Column chromatography on 48 g of
silica gel (elution with 5e20% Et2Oepentane) afforded 0.061 g
(30%) of cyclooctatrienone 8 as a yellow oil and 0.075 g (36%) of
indan 13 as a yellow oil. For cyclooctatrienone 8: IR (neat) 3301,
2955, 2916, 2844, 1661, 1615, 1564, 1434, 1286, 1234, 1200, 1029,
and 820 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
6.61 (d, J¼13.3 Hz, 1H),
6.36e6.41 (m, 2H), 2.91 (br s, 2H), 2.49 (app q, J¼7.5 Hz, 4H), 2.11 (s,
3H), 1.93 (quint, J¼7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 190.9,
141.4, 139.7, 139.4, 135.4, 132.9, 130.0, 44.4, 36.7, 35.8, 26.7, 23.1;
HRMS-ESI (m/z) [MþNa]þ calcd for C12H14O: 197.0937, found:
197.0935. For indan 13:2a 1H NMR (400 MHz, CDCl3)
d 7.47 (s, 1H),
7.24 (s, 1H), 3.21 (t, J¼7.4 Hz, 2H), 2.88 (t, J¼7.6 Hz, 2H), 2.58 (s, 3H),
2.37 (s, 3H), 2.07 (quint, J¼7.5 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
200.3, 146.6, 142.6, 136.0, 133.9, 129.6, 128.3, 33.9, 32.4, 28.6, 25.5,
21.3.
4.6. [4D4] Annulations with acylcyclobutenes
4.6.1. (5Z,7Z)-6-Methyl-3,4,9,10-tetrahydrobenzo[8]annulen-1(2H)-
one (26). Method A: A 250-mL, three-necked, round-bottomed
flask equipped with an argon inlet adapter, two rubber septa, and
a thermocouple probe was charged with enone 21 (0.107 g,
0.569 mmol, 1.0 equiv) and 57 mL of CH2Cl2. The reaction mixture
was cooled to ꢁ78 ꢀC and methanesulfonic acid solution (0.24 M in
CH2Cl2, 2.35 mL, 0.57 mmol, 1.0 equiv) was added dropwise over
5 min. The yellow reaction mixture was stirred at ꢁ78 ꢀC for 4 h,
and then 10 mL of satd aq NaHCO3 solution was added dropwise
over 5 min. The resulting mixture was warmed to 0 ꢀC and then
diluted with 10 mL of brine. The organic phase30 was dried over
Na2SO4 and filtered into a threaded Pyrex tube (28 mm I.D., 35 mm
O.D., 20-cm long). The pale blue reaction mixture was de-
oxygenated with a stream of argon for 5 min, and then the tube was
sealed with a threaded Teflon cap. The reaction mixture was heated
at 70 ꢀC for 5 h, and then cooled to rt and concentrated to give
0.125 g of brown oil. Purification by column chromatography on
16 g of silica gel (elution with 8% EtOAcehexanes) afforded 0.074 g
(69%) of cyclooctatriene 26 as a yellow oil: IR (neat) 3307, 2932,
1663, 1609, 1433, 1374, 1299, 1176, 1128, 819, 756, and 718 cmꢁ1; 1H
4.6.2. (5Z,7Z)-3,4,9,10-Tetrahydrobenzo[8]annulen-1(2H)-one
(27). A 250-mL, three-necked, round-bottomed flask equipped
with an argon inlet adapter, two rubber septa, and a thermocouple
probe was charged with enone 20 (0.150 g, 0.861 mmol, 1.0 equiv)
and 80 mL of CH2Cl2. The reaction mixture was cooled to ꢁ30 ꢀC
and methanesulfonic acid solution (0.24 M in CH2Cl2, 3.6 mL,
0.86 mmol, 1.0 equiv) was added over 4 min. The reaction mixture
was stirred at ꢁ30 to ꢁ15 ꢀC for 2.5 h and then 50 mL of satd aq
NaHCO3 solution was added in one portion. The organic layer was
separated and washed with 50 mL of satd aq NaHCO3, dried over
Na2SO4, filtered, and concentrated to give a yellow oil.31 This ma-
terial was dissolved in 80 mL of CH2Cl2 and transferred to a threa-
ded Pyrex tube (28 mm I.D., 35 mm O.D., 20-cm long) equipped
with a stir bar, rubber septum, and an argon inlet needle. Cam-
phorsulfonic acid (0.400 g, 1.72 mmol, 2.0 equiv) was added and
the solution was deoxygenated with a stream of argon for 5 min.
The tube was sealed with a threaded Teflon cap. The reaction
NMR (400 MHz, CDCl3)
d
5.72 (d, J¼13.3 Hz, 1H), 5.69 (s, 1H), 5.60

J.M. Robinson et al. / Tetrahedron 67 (2011) 9890e9898
9897
mixture was heated at 100 ꢀC for 15 h and then cooled to rt and
concentrated to give a brown oil. Purification by column chroma-
tography on 15 g of silica gel (elution with 3% Et2Oepentane)
afforded 0.083 g (55%) of cyclooctatriene 27 as a yellow oil: IR
(neat) 3001, 2932, 2875, 2832, 1661, 1432, 1176, 680 cmꢁ1; 1H NMR
1436,1372,1300,1240,1177, 1127,1100,1025, 956, 917, 854, 821, and
733 cmꢁ1 1H NMR (400 MHz, CDCl3)
5.66 (s, 1H), 5.42 (t,
;
d
J¼4.3 Hz, 1H), 2.41 (t, J¼6.7 Hz, 2H), 2.52 (t, J¼6.4 Hz, 2H), 2.34 (t,
J¼5.9 Hz, 2H), 2.29 (t, J¼6.0 Hz, 2H), 2.03e2.11 (m, 2H), 1.95 (quint,
J¼6.4 Hz, 2H), 1.60e1.74 (m, 4H); 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3)
5.68e5.76 (m, 1H), 2.58 (t, J¼5.8 Hz, 2H), 2.45 (t, J¼6.7 Hz, 2H),
2.35e2.46 (m, 2H), 2.34 (t, J¼6.0 Hz, 2H), 2.00 (quint, J¼6.3 Hz, 2H);
d
5.96 (dd, J¼12.2, 5.9 Hz, 1H), 5.79e5.89 (m, 2H),
d 199.2, 155.6, 145.0, 137.0, 136.2, 124.0, 122.5, 41.6, 38.7, 38.2, 30.4,
28.9, 28.5, 28.2, 23.8, 23.0; HRMS-DART (m/z) calcd for C16H20
O
[MþH]þ: 229.1592, found: 229.1590.
13C NMR (100 MHz, CDCl3)
d 198.8, 154.2, 137.6, 135.2, 128.9, 128.3,
123.3, 37.9, 30.3, 30.0, 23.5, 22.8; HRMS-DART (m/z) calcd for
Acknowledgements
[MþH]þ: 175.1117, found: 175.1121.
We thank the National Institutes of Health (GM 28273) and
Pfizer Inc. for generous financial support. J.M.R and J.F. were sup-
ported in part by National Science Foundation Graduate Fellow-
ships. J.M.R. was supported in part by an AstraZeneca Graduate
Fellowship and a David A. Johnson Summer Graduate Fellowship.
4.6.3. (3aZ,11Z)-2,3,5,6,9,10-Hexahydro-1H-benzo[a]cyclopenta[d][8]
annulen-7(8H)-one (38). A 250-mL, three-necked, round-bottomed
flask equipped with an argon inlet adapter, two rubber septa, and
a thermocouple probe was charged with enone 22 (0.095 g,
0.44 mmol, 1.0 equiv) and 44 mL of CH2Cl2. The reaction mixture
was cooled to ꢁ78 ꢀC and 1.82 mL of methanesulfonic acid solution
(0.24 M in CH2Cl2, 0.44 mmol, 1.0 equiv) was added dropwise over
1 min. The pale yellow reaction mixture was stirred at ꢁ78 ꢀC for
1 h, and then additional methanesulfonic acid solution (0.24 M in
CH2Cl2, 0.90 mL, 0.22 mmol, 0.50 equiv) was added. After 30 min at
ꢁ78 ꢀC, the reaction mixture was warmed to ꢁ60 ꢀC, stirred for 1 h,
and then additional methanesulfonic acid solution (0.24 M in
CH2Cl2, 0.90 mL, 0.22 mmol, 0.5 equiv) was added. The green re-
action mixture was stirred at ꢁ60 ꢀC for 3 h, and then 10 mL of satd
aq NaHCO3 solution was added and the resulting mixture was
warmed to 0 ꢀC over 10 min. The blue organic phase32 was sepa-
rated, dried over Na2SO4, and then filtered into a threaded Pyrex
tube (35 mm O.D.; 28 mm I.D.; 15-cm long) equipped with a stir
bar, rubber septum, and an argon inlet needle. The solution was
deoxygenated with a stream of argon for 5 min and then the tube
was sealed with a threaded Teflon cap. The reaction mixture was
heated at 70 ꢀC for 3 h, and then cooled to rt and concentrated to
give 0.124 g of green oil. Purification by column chromatography on
16 g of silica gel (elution with 3e8% EtOAcehexanes) afforded
0.038 g (40%) of cyclooctatriene 38 as an orange oil: IR (neat) 2929,
1659, 1601, 1433, 1370, 1327, 1299, 1175, 1127, 920, 815, and
References and notes
1. For a review, see Wessig, P.; Muller, G. Chem. Rev. 2008, 108, 2051e2063.
2. For earlier work in this area from our laboratory, see (a) Danheiser, R. L.; Gould,
A. E.; Fernandez de la Pradilla, R.; Helgason, A. L. J. Org. Chem. 1994, 59,
5514e5515; (b) Wills, M. S. B.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120,
9378e9379; (c) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127,
5776e5777; (d) Hayes, M. E.; Shinokubo, H.; Danheiser, R. L. Org. Lett. 2005, 7,
3917e3920.
3. For reviews on cyclic cumulenes, see: (a) Johnson, R. P. Chem. Rev. 1989, 89,
1111e1124; (b) Christl, M. Cyclic Allenes Up to Seven-Membered Rings In
Modern Allene Chemistry; Krause, N., Hashmi, S. K., Eds.; Wiley-VCH: Weinheim,
2004; pp 243e357; (c) Kawase, T. Cyclic Allenes In. Science of Synthesis; Krause,
N., Ed.; Thieme: Stuttgart, 2007; Vol. 44, pp 395e449; (d) Johnson, R. P.;
Konrad, K. M. Strained Cyclic Allenes and Cumulenes In Strained Hydrocarbons;
Dodziuk, H., Ed.; Wiley-VCH: Weinheim, 2009; pp 122e146.
4. The intermediacy of strained cyclic allenes in these reactions is supported by
experimental observations and computational studies. See Refs.1,2a, and Ana-
nikov, V. P. J. Phys. Org. Chem. 2001, 14, 109e121.
5. Reviews: (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757e5821; (b)
Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881e930; (c) Yu, Z.; Wang, Y.; Wang, Y.
Chem.dAsian J. 2010, 5, 1072e1088.
6. For a review of [4þ4] cycloaddition strategies, see Sieburth, S. M.; Cunard, N. T.
Tetrahedron 1996, 52, 6251e6282.
7. For an earlier [4þ4] annulation strategy developed in our laboratory, see:
Danheiser, R. L.; Gee, S. K.; Sard, H. J. Am. Chem. Soc. 1982, 104, 7670e7672.
8. For the construction of eight-membered carbocyclic systems via the [4þ4]
photocycloaddition of enynes with 2-pyridones, see Kulyk, S.; Dougherty, W.
G.; Kassel, W. S.; Fleming, S. A.; Sieburth, S. M. Org. Lett. 2010, 12, 3296e3299.
9. Reviewed in Marvell, E. B. Thermal Electrocyclic Reactions; Academic: New York,
NY, 1980.
10. Reviews: (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006; (b) Tietze, L. F.; Beifuss, U. Angew.
Chem., Int. Ed. Engl. 1993, 32, 131e163; (c) Bunce, R. A. Tetrahedron 1995, 51,
13103e13159; (d) Tietze, L. F. Chem. Rev. 1996, 96, 115e136.
11. For examples of DielseAlder [4þ2] cycloadditions involving cyclobutenones,
see (a) Kelly, T. R.; McNutt, R. W. Tetrahedron Lett. 1975, 16, 285e288; (b) Bi-
enfait, B.; Coppe-Motte, G.; Merenyi, R.; Viehe, H. G. Tetrahedron 1991, 47,
8167e8176; (c) Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 11004e11005.
12. Wasserman, H. H.; Piper, J. U.; Dehmlow, E. V. J. Org. Chem. 1973, 38, 1451e1455.
13. Prepared by Sonogashira coupling of 4-pentyn-1-ol with 2-bromopropene as
described by Hashmi, A. K. S.; Sinha, P. Adv. Synth. Catal. 2004, 346, 432e438.
14. Hydrolysis of the intermediate vinylogous hemiacetal generated in the orga-
nolithium addition to 3-ethoxycyclobutenone was best accomplished using the
general protocol of Liebeskind, L. S.; Wirtz, K. R. J. Org. Chem. 1990, 55,
5350e5358.
15. Reviewed in Danheiser, R. L.; Dudley, G. B.; Austin, W. F. Alkenylketenes In.
Science of Synthesis; Danheiser, R. L., Ed.; Thieme: Stuttgart, 2006; Vol. 23,
pp 493e568.
16. The structure of 8 was confirmed by spectroscopic analysis, including com-
parison of its IR and proton and carbon NMR data with that reported for 2,4,6-
cyclooctatrienone. See (a) Adam, W.; Cueto, O.; De Lucchi, O. Chem. Ber. 1982,
115, 1170e1177; (b) Meier, H.; Lorch, M.; Petersen, H.; Gugel, H. Chem. Ber. 1982,
115, 1418e1424.
17. For several key and especially relevant examples, see (a) Cope, A. C.; Haven, A.
C.; Ramp, F. L.; Trumbull, E. R. J. Am. Chem. Soc. 1952, 74, 4867e4871; (b)
Huisgen, R.; Boche, G.; Dahmen, A.; Hetchl, W. Tetrahedron Lett. 1968, 9,
5215e5219; (c) Wagner, P. J.; Nahm, K. J. Am. Chem. Soc. 1987, 109, 6528e6530;
(d) Fujiwara, T.; Ohsaka, T.; Inoue, T.; Takeda, T. Tetrahedron Lett. 1988, 29,
6283e6286; (e) Computational study: Fry, A. Tetrahedron 2008, 64, 2101e2103.
18. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815e3818.
19. Reviewed in (a) Sibi, M. P. Org. Prep. Proceed. Int. 1993, 25, 15e40; (b) Balasu-
bramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707e3738.
732 cmꢁ1
; d 5.81e5.89 (m, 1H),
1H NMR (400 MHz, CDCl3)
5.76e5.80 (m, 1H), 2.61 (td, J¼7.5, 1.6 Hz, 2H), 2.51e2.57 (m, 2H),
2.39e2.46 (m, 6H), 2.34 (t, J¼6.0 Hz, 2H), 1.90 (quint, J¼6.3 Hz, 2H),
1.65 (quint, J¼7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 199.1, 154.9,
145.2, 137.2, 136.5, 129.4, 122.8, 38.05, 38.04, 37.9, 32.0, 31.4, 23.6,
23.1, 21.9; HRMS-DART (m/z) calcd for C15H18O [MþH]þ: 215.1430,
found: 215.1423.
4.6.4. (7Z,11aZ)-2,3,5,6,8,9,10,11-Octahydrodibenzo[a,d][8]annulen-
4(1H)-one (39). A 250-mL, three-necked, round-bottomed flask
equipped with an argon inlet adapter, two rubber septa, and
a thermocouple probe was charged with enone 23 (0.017 g,
0.47 mmol, 1.0 equiv) and 47 mL of CH2Cl2. The reaction mixture
was cooled to ꢁ78 ꢀC and 2.02 mL of methanesulfonic acid solution
(0.24 M in CH2Cl2, 0.489 mmol, 1.0 equiv) was added dropwise over
2 min. The reaction mixture was stirred at ꢁ78 ꢀC for 3 h, and then
10 mL of satd aq NaHCO3 solution was added dropwise over 5 min.
The reaction mixture was warmed to 0 ꢀC over 10 min, and then
diluted with 10 mL of brine. The organic phase33 was separated and
dried over Na2SO4 and then filtered into a threaded Pyrex tube
(35 mm O.D.; 28 mm I.D.; 15-cm long) equipped with a stir bar,
rubber septum, and an argon inlet needle. The solution was de-
oxygenated with a stream of argon for 5 min and then the tube was
sealed with a threaded Teflon cap. The reaction mixture was heated
at 70 ꢀC for 14 h, and then cooled to rt and concentrated to give
0.112 g of brown oil. Purification by column chromatography on
17 g of silica gel (elution with 5% EtOAcehexanes) provided 0.028 g
(26%) of cyclooctatriene 39 as an orange oil: IR (neat) 2248, 1663,

9898
J.M. Robinson et al. / Tetrahedron 67 (2011) 9890e9898
20. Song, A.; Parker, K. A.; Sampson, N. S. J. Am. Chem. Soc. 2009, 131, 3444e3445.
21. Prepared by hydrolysis of commercially available TIPPSO2Cl as described by
Jautze, S.; Peters, R. Angew. Chem., Int. Ed. 2008, 47, 9284e9288 The acid was
dried over P2O5 under vacuum (0.1 mmHg) for 48 h prior to use.
22. Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D. Angew. Chem., Int. Ed.
2008, 47, 8100e8103.
30. In a separate run, the organic phase was concentrated to give 0.055 g of brown oil
that was determined to be diene 24: IR (neat) 2936, 1707, 1442, 1365, 1333, 1195,
1020, 885, and 734 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
6.07 (s,1H), 5.68 (dd, J¼6.9,
3.8 Hz, 1H), 3.43 (q, J¼8.2 Hz, 1H), 2.50e2.60 (m, 2H), 2.30e2.38 (m, 2H), 2.14e2.
28 (m, 4H),1.82e1.88 (m, 2H),1.79 (s, 3H); 13C NMR (400 MHz, CDCl3)
d 212.9,138.
7, 134.4, 122.7, 120.9, 50.6, 35.1, 34.1, 33.1, 29.4, 24.5, 22.4, 21.4.
23. Acylcyclobutene 30 was prepared beginning from 4-butyn-1-ol by a route
analogous to that employed for the synthesis of the homologous substrates
described in Scheme 4.
24. A similar difference is observed in the rate of intramolecular DielseAlder re-
actions. Cycloaddition of 1,7,9-decatrien-3-one (four-atom tether) produces the
expected octalone below rt, while reaction of 1,6,8-nonatrien-3-one (with
a three-atom tether) requires 180 ꢀC. The diminished rate of cycloaddition in
the three-atom tether series has been attributed to increased steric interactions
in the connecting chain and to diminished overlap of the carbonyl group with
31. The product of a separate run was purified by silica gel using 3% Et2Oehexane
elution to afford the diene 25: IR (neat) 2226, 1707, 1432, 1330, 1193, 1072, 899,
821, and 736 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
6.30 (td, J¼10.0, 2.6 Hz, 1H), 5.
79 (dd, J¼6.6, 3.7 Hz), 5.65e5.75 (m, 1H), 3.44 (q, J¼8.2 Hz, 1H), 2.50e2.62 (m,
2H), 2.33e2.50 (m, 2H), 2.09e2.33 (m, 2H), 1.97e2.09 (m, 2H) 1.77e1.87 (m,
2H); 13C NMR (100 MHz, CDCl3)
d 212.4, 138.0, 127.6, 125.9, 123.4, 51.5, 34.9, 34.
3, 28.8, 28.0, 22.5, 21.3. HRMS-DART (m/z) calcd for [MþNa]þ: 197.0937, found:
197.0940.
32. This organic phase is presumed to contain diene 36. In a separate run, the
organic phase was concentrated to afford 0.009 g of yellow oil that was shown
to be a mixture of enyne 22 and diene 36. The diene is characterized by the 1H
NMR resonances at 5.62 ppm (s, 1H) corresponding to the alkenyl proton and 3.
75e3.83 (m, 1H) corresponding to the allylic methine proton. Diene 40 was
observed in the mixture of products of another run and identified by charac-
teristic 1H NMR alkene resonances at 5.90e5.98 (m, 1H) and 5.70 ppm (s, 1H).
33. The organic phase is presumed to contain diene 37. In a separate run, the or-
ganic phase was concentrated to afford 0.012 g of brown oil that was shown to
be a mixture of diene 37 and other compounds. This diene is characterized by
the 1H NMR resonances at 5.58 ppm corresponding to the alkenyl proton and 3.
55 ppm corresponding to the allylic methine proton.
the dienophilic p-bond. See (a) Jung, M. E.; Halweg, K. M. Tetrahedron Lett. 1981,
22, 3929e3932; (b) Smith, D. A.; Sakan, K.; Houk, K. N. Tetrahedron Lett. 1986,
27, 4877e4880.
25. Esters 31 and 32 were prepared by reaction of cyclobutenecarboxylic acid with
oxalyl chloride followed by addition of the appropriate enynyl alcohol.
26. (a) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165e167; (b) Ellison,
R. A.; Griffin, R.; Kotsonis, F. N. J. Organomet. Chem. 1972, 36, 209e213.
27. Stanislawski, P. C.; Willis, A. C.; Banwell, M. G. Org. Lett. 2006, 8, 2143e2146.
28. Tessier, P. E.; Nguyen, N.; Clay, M. D.; Fallis, A. G. Org. Lett. 2005, 7, 767e770.
29. Weinreb amide 19 is sparingly soluble in Et2Oepentane mixtures at ꢁ78 ꢀC so
THF was added to form a homogeneous reaction mixture.