Intermolecular [8+2] cycloaddition reactions of 2H-3-methoxycarbonylcyclohepta[b]furan-2-one with vinyl ethers: An approach to bicyclo[5.3.0]azulene derivatives

Article abstract of DOI:10.1016/S0040-4039(01)02061-5

Substituted bicyclo[5.3.0]azulene compounds are synthesized by intermolecular [8+2] cycloaddition reactions of lactone 1 with vinyl ethers - acetal decomposition products - are described. The reactions were found to be temperature and solvent dependent.

Full text of DOI:10.1016/S0040-4039(01)02061-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 19–20
Intermolecular [8+2] cycloaddition reactions of
2H-3-methoxycarbonylcyclohepta[b]furan-2-one with vinyl ethers:
an approach to bicyclo[5.3.0]azulene derivatives
Wellington Pham, Ralph Weissleder and Ching-Hsuan Tung*
Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, 149 13th Street,
Charlestown, MA 02129, USA
Received 16 July 2001; revised 15 October 2001; accepted 16 October 2001
Abstract—Substituted bicyclo[5.3.0]azulene compounds are synthesized by intermolecular [8+2] cycloaddition reactions of lactone
1 with vinyl ethers—acetal decomposition products—are described. The reactions were found to be temperature and solvent
dependent. © 2001 Elsevier Science Ltd. All rights reserved.
we report an improved procedure toward the synthesis
of the [5.3.0] ring system of azulenes (Scheme 1).
Azulene compounds have recently attracted attention
due to their specific physical and chemical properties.1
Depending on the substituents attached to the rings,
azulene derivatives have a range of color spectra from
red, blue, purple to green. The aromaticity of the
five-membered ring of azulene has been a subject for
several important modifications, namely Friedel–Crafts
acylation, Mannich aminomethylation, condensation,
Vilsmeier formylation, among others. An azulene ring
has been synthesized by cycloaddition reactions of the
activated troponoid and the active methylene com-
pound.2 In addition to the [6+4] addition mode, some
of these systems are known to undergo [8+2] cycloaddi-
tion.2 In an effort to synthesize azulene derivatives as
chromophores, we were interested in starting with the
lactone 1. There are few reports for the synthesis of
azulene compounds.2 However, for the reaction inter-
mediate, conditions had not been clearly defined, result-
ing in unreproducible results. In this communication,
Upon thermolysis, the acetal 2 was decomposed into
the active vinyl ether 4 and methanol. The cycloaddi-
tion reaction between the lactone 1 and 4 forms azulene
3 as a single product.
The yield of the product was significantly improved by
optimizing the reaction conditions. For this type of
acetal the thermal decomposition usually requires
highly pressurized conditions.3 In addition, we found
the reaction was homogeneous at high temperature,
and methanol released from the decomposition did not
Scheme 1.
* Corresponding author. E-mail: tung@helix.mgh.harvard.edu
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02061-5

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W. Pham et al. / Tetrahedron Letters 43 (2002) 19–20
Table 1.
Entry
Reactant
Product
Yield (%)
umax (nm) MeCN
Neata
140°C
160°C
200°C
1
2
3
2a
2b
2c
3a
3b
3c
Dec.b
Dec.b
Dec.b
40
0c
0c
81
0c
0c
100
86
60
524
535
559
a 200°C.
b Dec., decomposed.
c Lactone 1 can be recovered by flash column chromatography.
reverse the reaction nor did it react with the reactants.
Contradictory to previous reports2 the reaction could
not be carried out neat in most of the syntheses. In the
absence of toluene the expected brownish–red liquid
products did not form. Instead, black tar-like decompo-
sition material was recovered. This observation suggests
that solvation of the vinyl ether is needed for the
cycloaddition step to proceed. Initially, we thought the
reaction could be done neat if the thermolysis product
of the vinyl ether was a gas. Therefore, we decided to
start with 2b as a model experiment. However, the
observation was consistent to that of 2a (Table 1). The
activation volume under high pressure is similar to that
of a typical Diels–Alder reaction in these reactions,
which proves that high pressure is effective for enhanc-
ing reactivity.4 At high temperature (200°C) and high
pressure we isolated product 3a in 100% yield by flash
column chromatography. The yield was diminished at
lower temperature. In the characterization of the prod-
(t, J=11.1 Hz, 1H), 7.50 (t, J=11.1 Hz, 1H), 7.69 (t,
J=11.1 Hz, 1H), 8.28 (d, J=10.6 Hz, 1H), 9.48 (d,
J=10.6 Hz, 1H); MS (MALDI-TOF) calcd: 200,
found: 201 (M+H)+; UV (MeCN) umax 524 nm.
1
Compound 3b: H NMR (200 MHz, CDCl3): l 3.96 (s,
3H), 7.33 (d, J=5.0 Hz, 1H), 7.45 (t, J=10.1 Hz, 1H),
7.55 (t, J=10.5 Hz, 1H), 7.81 (t, J=9.8 Hz, 1H), 8.37
(d, J=4.5 Hz, 1H), 8.46 (d, J=10.5 Hz, 1H), 9.66 (d,
J=10.5 Hz, 1H); MS (MALDI-TOF) calcd: 186,
found: 187 (M+H)+; UV (MeCN) umax 535 nm.
1
Compound 3c: H NMR (200 MHz, CDCl3): l 2.63 (s,
3H), 3.98 (s, 3H), 7.26–7.50 (m, 2H), 7.79 (t, J=9.2 Hz,
1H), 8.2 (s, 1H), 8.37 (d, J=9.2 Hz, 1H), 9.55 (d,
J=9.2 Hz, 1H); MS (MALDI-TOF) calcd: 200, found:
200 (M+H)+; UV (MeCN) umax 559 nm.
1
Acknowledgements
ucts by H NMR spectroscopy, a first order splitting
pattern of the AX system was observed.
We would like to thank Dr. Tatsushi Toyokuni for
helpful discussions and Dr. Steven M. Peseckis for
technical support. This work was supported by
National Institute of Health grants CA66355 and
CA88365.
In summary, we demonstrate a convenient synthesis of
the [5.3.0] bicyclo systems of azulene derivatives. The
yield was significantly improved under high tempera-
ture and pressure in the presence of aprotic solvent.
The azulene products 3 are key intermediates for syn-
thesizing diagnostic and potential therapeutic agents.
Finally this work may contribute to the synthesis of
more complex systems of a similar type.
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1
viscous liquid 3a (3.92 g, 100%); H NMR (400 MHz,
CDCl3): l 2.83 (s, 3H), 3.98 (s, 3H), 7.13 (s, 1H), 7.39