S. Yan et al. / Tetrahedron Letters 52 (2011) 465–467
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The results in Table 2 demonstrate that HKAs, with various sub-
stituents (15a–k), were all good substrates for the reaction. The
substituents of the HKAs 15 had slight influence on the reactivity
and product yield. The yields of all substrates are all similar
(Table 2, entries 1–11).
Additionally, in terms of the ring sizes of the HKAs 15, the yields
of the seven-membered HKAs was superior to that of the five-mem-
bered and the six-membered HKAs (entries 8–11 vs 1–3 and 4–7).
All new compounds 17 were fully characterized on the basis of
their 1H, 13C NMR spectra, and high resolution mass spectra,36
which indicated that the HKAs reacted with 2,2-dihydroxy-2H-
indene-1,3-dione in a 1:1 ratio, affording novel kinds of tetracy-
clo-isocoumarins.
To verify the structure of the tetracyclo-isocoumarin products,
17h was selected as a representative compound and characterized
by X-ray crystallography, as shown in Figure 2 (CCDC 781822).37
A proposed mechanism of the acetic acid-catalyzed cascade
reaction is depicted in Scheme 3. Firstly, carbonyl group of 2,2-
dihydroxy-2H-indene-1,3-dione 16 accepted one proton of to form
18. Then the reaction of HKAs 15, due to the strongly electron-
withdrawing groups at the
a-position of the ketene N,N-acetals
acted as heteroene components, with 18 proceeded via an aza-
ene addition to afford 19. The intermediate 19 was followed by
imine–enamine tautomerization, intramolecular cyclization, and
dehydration to get 20. The adjacent OH undergoes intramolecular
attack on the carbonyl group to obtain a hydroxy epoxide interme-
diate 21, which through proton transfer is able to produce 22. Sub-
sequently ring-enlargement reaction occurs through opening of
the epoxide ring with losing a molecule of H2O to get 23. Finally,
23 loses proton to result in the target product 17.
In conclusion, we developed a procedure for the simple synthe-
sis of a variety of potential, biologically active tetracyclo-iso-
coumarins. Using this method, a molecularly diverse tetracyclo-
isocoumarin library was rapidly constructed with good yields by
simply refluxing a reaction mixture of HKAs and 2,2-dihydroxy-
2H-indene-1,3-dione, catalyzed by AcOH.
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20. Venkatesh, C.; Reissig, H.-U. Synthesis 2008, 3605.
21. Harris, T. M.; Harris, C. M.; Oster, T. A.; Brown, L. E., Jr.; Lee, J. Y. C. J. Am. Chem.
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4829.
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5274.
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Acknowledgments
The authors acknowledge the financial support in the form of
grants from NSFCs (Nos. 30860342 and 20762013) and NSFYNs
(Nos. 2009cc017 and 2008cd063).
Supplementary data
35. (a) Opatz, T.; Ferenc, D. Eur. J. Org. Chem. 2005, 817; (b) Mal, D.;
Bandyopadhyay, M.; Ghorai, S. K.; Datta, K. Tetrahedron Lett. 2000, 41, 3677.
36. General procedure for the synthesis of compounds 17. HKAs 15 (2.5 mmol),
2,2-dihydroxy-2H-indene-1,3-dione 16 (2.75 mmol), and 1,4-dioxane (15 mL)
were charged into a 50 mL round-bottomed flask, then acetic acid (3 mL) was
added to the mixture and the mixture was refluxed. The resulting solution was
stirred for 4–6 h until the HKAs 15 were completely consumed. The mixture
was cooled to room temperature, neutralized with a saturated solution of
Na2CO3 to pH 8–9, and then EtOAc (50 mL Â 2) was added. The organic phase
was washed with water (10 mL), dried over Na2SO4, concentrated, and purified
by flash column chromatography to afford tetracyclo-isocoumarins 17 in a
71À89% yield. Compound 17a: yellow solid; 81% mp: 140–144 °C. IR (KBr):
Supplementary data associated with this article can be found, in
References and notes
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3437, 2979, 1723, 1678, 1600, 1455, 1320, 1130, 765 cmÀ1 1H NMR (500 MHz,
.
CDCl3): d = 1.41 (t, J = 7.0 Hz, 3H, CH3), 4.09 (t, J = 7.5 Hz, 2H, NCH2), 4.21 (t,
J = 7.5 Hz, 2H, NCH2), 4.34 (t, J = 7.0 Hz, 2H, OCH2), 4.94 (s, 1H, NH), 7.31 (t,
J = 7.3 Hz, 1H, ArH), 7.70 (t, J = 7.3 Hz, 1H, ArH), 8.27 (d, J = 7.9 Hz, 1H, ArH),
9.01 (d, J = 7.9 Hz, 1H, ArH). 13C HMR (125 MHz, CDCl3): d = 15.2, 43.8, 49.2,
60.0, 84.5, 99.6, 117.4, 125.3, 125.5, 131.3, 135.6, 137.0, 150.1, 161.6, 164.9,
196.2. HRMS (TOF ES+): m/z calcd for C16H14N2NaO4 [(M+Na)+], 321.0846;
found, 321.0840.
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37. CCDC 781822 contains the supplementary crystallographic data for compound
17h. These data can be obtained free of charge from The Cambridge