Organic Letters
Letter
1
Full experimental details; H and 13C NMR spectra
Scheme 3. Total Synthesis of the IPK Precursor 1
AUTHOR INFORMATION
Corresponding Author
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ORCID
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Dr. M. Gulea (UMR7200) and Dr. G. Blond
(UMR7200) for assistance in the preparation of this
manuscript. S.-Q.T. gratefully acknowledges the Ministry of
Education of the P.R. China for financial support of this
work (China Scholarship Council (201608310124)).
REFERENCES
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followed by the debromination of positions 4 and 6 by AlCl3,
led to the desired 3-bromo-2,5-dimethylphenol. Following a
subsequent O-methylation step, 7 was obtained in a 74%
overall yield (three steps). Radical bromination of the methyl
group at position 2 then gave organozinc 6c, which was stored
in THF. Subsequently, 2-bromo-3-methoxybenzoic acid was
coupled to ethyl acetoacetate in the presence of a catalytic
amount of copper bromide. While sodium ethanolate is
required for the copper-mediated coupling reaction, it also
promoted an in situ deacetylation to afford 2b in a 94% yield.
Following formation of the thioester 3j under standard
conditions, a Fukuyama CCR was performed with organozinc
6c using POxAP PdCl(Ph)(PPh3)2 to give 4k in 82% yield,
which was oxidized by SeO2 in AcOH.16 Several conditions
were then attempted for the subsequent cyclization. While
TEA in hot ethanol produced 9a (Table 1), the unsubstituted
analogue of 9b, the steric hindrance imparted by both aromatic
rings of 8b prevented the formation of 9b itself. Several
conditions were examined (see the SI), but only the use of
DBU in hot DMSO led to indanone 9b in an excellent yield.
Finally, a palladium-catalyzed cyanation reaction led to the
desired IPK precursor 1. This compound was synthesized over
11 steps and in an overall yield of 29%. This compares to a 3%
overall yield from 16 steps as reported previously.2e
In conclusion, we demonstrated that the POxAPs of generic
formula PdX(Ar)(PPh3)2, prepared from the oxidative addition
of Pd(0) with ArX, constituted efficient Pd(II) precatalysts.
Indeed, these bench stable POxAPs could be employed in
particularly low quantities (0.001 mol %) to perform
Fukuyama CCRs and generate a large diversity of ketones.
This efficacy was demonstrated through the development of a
convenient route to IPK. The use of these POxAP are not
limited to the Fukuyama CCR, and their efficacies in other
palladium-catalyzed CCRs are currently under investigation.
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ASSOCIATED CONTENT
* Supporting Information
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