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Angewandte
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ring opening in order to generalize the above sequence for the
formation of bicyclic systems containing medium and macro-
cyclic rings fused to lactones. Of particular interest was the
hypothesis that the ring opening of larger [n.2.0] substrates
would lead to isolable cis,trans-bicyclic lactones (see com-
pound 5), thus confirming the conrotatory mode of ring
opening in these fused systems.
While the 6-membered anhydride 1 and its 5-membered
homologue are readily obtainable, none of the higher
members were commercially available. Fortunately, we were
able to exploit the versatile methodology of Tanaka[18] to
synthesize a range of cyclic anhydride derivatives. This
method involved subjecting b-keto-ester-derived enol-tri-
flates to a palladium-catalyzed carbonylation sequence, and
gave us access to a number of isolated anhydrides 7 in good
yields. These were then subjected to [2+2] photocycloaddi-
tion with propargyl alcohols using a medium-pressure 400 W
Hg lamp in a water-cooled pyrex immersion well.
Generally, the photocycloadditions proceeded smoothly,
allowing the isolation of the corresponding cyclobutenes 8 in
moderate to good yields and in multigram quantities. Further
scale-up could be achieved using our flow photochemistry
techniques,[19] which allowed for example the synthesis of 8b
with a productivity of 1.3 ghÀ1. Exceptions were observed
with the 9- and 12-membered examples 7 f and 7g, respec-
tively. Both anhydrides were photochemically very active and
were rapidly consumed upon irradiation to mainly unidenti-
fiable side products. However, a sufficient amount of the
cyclobutene could be synthesized for further study. Unfortu-
nately, a lack of suitable routes to the corresponding 10- and
11-membered anhydrides prevented their study. Rather
surprisingly, cycloaddition yields increased again with the
15-membered anhydride 7h. Once suitable quantities of the
cyclobutene anhydrides 8 were obtained, they were converted
to the substrates required for thermolysis (9) by simple acid-
catalyzed methanolysis (Table 1).
influenced by the size of the appended ring (Table 2).
Although the thermolysis of diesters 9a and 2 had been
studied in our previous work, we were able to optimize them
further. Thus, when the 5-membered system 9a (Table 2,
entry 1; R = H) was heated neat at 1808C, it gave the ring-
opened product in 25% yield (previously 6%) with high
recovery of the starting cyclobutene. Prolonged heating,
however, resulted in a reduced yield and extensive decom-
position. The 6-membered example (2, Table 2, entry 2, R =
H) also underwent slow but effective ring opening at 1408C in
xylenes to give the isolated cis,cis-cyclooctadiene 3 in an
improved yield of 95%. Heating 2 neat at 1808C for a shorter
period of time resulted in extensive decomposition before
maximum conversion could be achieved. The prolonged
reaction times and high temperatures needed for these
examples are undoubtedly linked to the highly strained
nature of the cis,trans-diene intermediates (see 5) formed by
conrotatory ring opening en route to the 7- and 8-membered
ring-opened systems.
It was pleasing, therefore, to observe the comparatively
rapid ring opening of the 7-membered homologue 9b at
1408C in xylene (Table 2, entry 3, R = H), which showed
about 40% conversion after 6 h. The optimization of this
reaction was achieved by simply heating 9b neat at 1808C,
which resulted in the formation of the cis,cis-diene product in
excellent yield (86%) in only 3 h. Interestingly, the methyl-
substituted example 9c underwent a similarly rapid ring-
opening/lactonization sequence. Previously we found that the
lower 6-membered homologue of this substrate failed to
undergo ring opening, which we attributed to unfavorable
transannular interactions in the initial cis,trans-cycloctadiene,
a factor that is clearly less of an issue with the larger
compound 9c. Increasing ring size led to a very significant
lowering of the activation energy, allowing the ring-opening/
lactonization sequence to 10d to occur at just 908C in 24 h
(Table 2, entry 5). A highly significant observation was that,
for the first time, the ring-opened product 10d had the
cis,trans-diene geometry, which was confirmed by X-ray
crystallography (see the Supporting Information). This obser-
vation clearly indicates a conrotatory ring opening and that
the 10-membered ring readily accommodates a trans-alkene,
thus obviating the need for it to undergo an isomerization as
would appear to be the case in the lower homologues. The
ethyl-substituted analogue 9e also underwent the sequence at
much lower temperatures (Table 2, entry 6). Very surpris-
ingly, the ring opening of the 9-, 12-, and 15-membered-ring
anhydrides 9 f–h occurred during the esterification process at
just 508C, and none of the cyclobutene diesters could be
isolated. These anhydrides gave the corresponding ring-
expanded lactones 10 f–h in reasonable to good overall
yields for one-pot, two-step processes. Once again, these
larger ring systems were obtained with the cis,trans-diene
geometry. Remarkably, the macrocyclic anhydride 9g was
found to undergo the electrocyclic ring-opening/lactonization
sequence in 30% yield after 10 days at 08C in the refriger-
ator! The high reactivity of the cyclobutene ring in these
macrocyclic fused systems is similar to some of the mono-
cyclic cyclobutenes studied previously by Houk.[17]
With a range of [n.2.0] bicyclic ring systems in hand, we
were now in a position to undertake a systematic study of the
thermolysis to see how the rate of electrocyclic ring opening is
Table 1: Preparation of [n.2.0]-fused bicyclic cyclobutenes for thermal
electrocyclic ring opening.
Entry
Anhydride
R
Yield 8 [%]
Yield 9 [%]
1
2
3
4
5
6
7
8
9
7a
1
n=1
n=2
n=3
n=3
n=4
n=4
n=5
n=8
n=11
H
H
H
Me
H
Et
H
H
H
70
67
60
55
62
57
18
21
50
74
84
80
77
80
7b
7c
7d
7e
7 f
7g
7h
42
see Table 2
see Table 2
see Table 2
2
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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