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Scheme 4 Transition state of the Cope rearrangement.
Scheme 2 Synthesis of a fused-indoline derivative.
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which affords cycloheptadiene derivatives. Compounds 3a–g
possessed an indolylvinyl cyclopropane structural motif, leading
us to investigate the construction of fused-polycyclic molecular
architectures through a Cope rearrangement of 3 (Table 3). The use
of various solvents to heat compound 3a revealed that 1,4-dioxane
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was the best solvent for this purpose and nitrogen-containing
fused-polycyclic compound 5a was obtained in 88% yield (entry 1).
Cope rearrangement of other substrates 3b–g was performed under
the same reaction conditions and the corresponding products 5b–g
were obtained in 51 to 83% yield (entries 2–7). The structure of 5a
11
was determined based on 2D-NMR and NOE experiments. The
Cope rearrangement via the boat transition state well rationalized
the observed results including the stereochemistry of the products
Scheme 3 Reaction pathway.
(
Scheme 4).
to give compound 3a as a kinetic product. This was probably
due to the proximity of both reactive sites in intermediate I. A
retro reaction from 3a to intermediate I also proceeded in the
presence of TBAF. The retro process proceeded more efficiently
when using DMF as the solvent. Compound 4a was formed
when the conjugate addition occurred from intermediate II, a
resonance structure of intermediate I. Irreversibility between 4a
and intermediate II resulted in the conversion from 3a to 4a.
cis-Divinyl cyclopropanes and structurally related cis-arylvinyl
cyclopropanes are effective substrates for Cope rearrangement,
We developed a novel method for synthesizing nitrogen-
containing fused-polycyclic compounds based on dearomatization
of phenols using tyramine derivatives as substrates. The formation
of allenyl spiro[5.5]cyclohexadienones through an intramolecular
ipso-Friedel–Crafts allenylation of phenols, followed by multiple
bond-forming–cleavage events initiated by the construction of an
indole skeleton, provided access to a wide variety of fused-polycyclic
molecules with unprecedented chemical architectures in reaction
sequences requiring only a few steps. The obtained products are of
potential interest as scaffolds for drug discovery. Further studies
are in progress to investigate the bioactivities of these molecules.
This work was financially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Sciences, and Technology, Japan, and Chiba University.
Table 3 Cope rearrangement of 3a–g
Notes and references
1
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2
a
2 For representative examples, see: (a) X. Zhang and R. C. Larock,
J. Am. Chem. Soc., 2005, 127, 12230; (b) F. Gonz ´a lez-L ´o pez de Turiso
and D. P. Curran, Org. Lett., 2005, 7, 151; (c) T. R. Ibarra-Rivera,
R. G ´a mez-Montano and L. D. Miranda, Chem. Commun., 2007, 3485;
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Y. Suzuki, R. Wu and Y. Hamada, Angew. Chem., Int. Ed., 2013,
Entry
Product
Time (h) Yield (%)
2
1
2
3
4
5
5a: R = H
18
9
11
13
15
88
79
65
62
73
2
5b: R = F
2
5c: R = OTs
2
5d: R = Cl
2
5e: R = COOMe
1
3
6
7
5f: R = CH
3
, R = H 20
83
51
52, 2217, and references sited therein.
1
3
5g: R = H, R = Cl 20
3
4
M. H. Zenk, M. Rueffer, M. Amann and B. Deus-Neumann, J. Nat.
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5
(
b) N. Kuroda, Y. Takahashi, K. Yoshinaga and C. Mukai, Org. Lett.,
a
Isolated yield.
2006, 8, 1843; (c) A. Saito, A. Kanno and Y. Hanzawa, Angew. Chem.,
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