Angewandte
Chemie
entry 6). For 1 f, the reaction became complicated upon
raising the reaction temperature. When R1 was a trimethyl-
silyl group, the desilylated product 3g was obtained in a
reasonable yield in which desilylation of 1g easily occurred
under basic condition[9] (Table 1, entry 7). In addition, reac-
tions with various substituents on the aryl ring of the 3-(1-
alkynyl)chromones proceeded smoothly (Table 1, entries 8–
11). However, the transformations of 1h and 1i, which has an
electron-withdrawing substituent, were carried out over a
prolonged reaction time of 10 hours.
Besides 2a, this tandem transformation can be success-
fully extended to various 1,3-dicarbonyl compounds, includ-
ing b-ketone esters and 1,3-diketones, thus leading to the
generation of the corresponding functionalized xanthones 4 in
60–82% yield (Table 2). Notably, the reactions proceed to
completion at room temperature over 3–6 hours. Clearly, in
this tandem reaction the ketone moiety can more easily
undergo 1,2-addition compared with the ester group. Inter-
estingly, the asymmetric 1-phenylbutane-1,3-dione can
undergo the tandem reaction to afford 4 f in 69% yield with
a high regioselectivity (Table 2, entry 6). The product 4 f was
confirmed by using X-ray crystal structure analysis (see the
Supporting Information).[8] A cyclic diketone was also
amenable to the tandem reaction and gave a polycyclic
product 4g in 75% yield (Table 2, entry 7). The results in
Table 1 and 2 clearly show that this novel tandem process
allows the generation of more complex xanthone-like natural
products under mild reaction conditions with various func-
tionalized groups, such as carbonyl, hydroxy, alkyl, and aryl
groups.
In conclusion, we have developed a novel base-promoted
tandem reaction to afford functionalized xanthones from 3-
(1-alkynyl)chromones with 1,3-dicarbonyl compounds under
mild reaction conditions. Notably, we found that this tandem
process involves multiple reactions, such as a Michael
addition-elimination/cyclization/1,2-addition/elimination
reactions, without the need for a transition metal catalyst.
This approach differs from previous reports that claimed a
furan is formed instead of a xanthone scaffold. Further library
generation and biological evaluation of the diversified
xanthones is under investigation.
Scheme 2. A proposed mechanism.
We examined the reaction of 1a with dimethyl malonate
2a under different reaction conditions (Table S1 in the
Supporting Information). When the reaction was carried out
in DMF, using NaH as the base at 458C, the product was
obtained in 70% yield. On carrying out the reaction at room
temperature for 10 hours, only a 30% yield of the product was
generated along with the intermediate 7a in 35% yield. By
increasing the reaction temperature to 458C, 7a can be
converted into the desired product 3a. These results support
our proposed mechanism that 7a has difficulty in undergoing
a 1,2-addition at room temperature. The yield was increased
to 82% when NaH and DIPEA were used in combination.
However, when only DIPEA (N,N-diisopropylethylamine)
was used as the base, a trace amount of the desired product
was observed along with recovered 1a. This outcome means
that a weak base cannot promote the initial Michael addition.
Also, when using the inorganic base K2CO3, the desired
product was obtained in 63% yield. Interestingly, when DBU
was employed, the yield increased significantly to 90%. A
modest decrease in the yield was observed on lowering the
amount of DBU from 3 equivalents to 1 equivalents, or on
changing the solvent to THF (tetrahydrofuran). The opti-
mized reaction conditions were defined with the reaction
carried out in DMF in the presence of DBU (3 equiv) at 458C
for 5 hours.
Experimental Section
A typical procedure for the preparation of 3a: A solution of dimethyl
malonate 2a (0.43 mmol) in dry DMF (3 mL) was added to DBU
(0.16 mL, 1.08 mmol) at room temperature under a nitrogen atmos-
phere. After stirring for 5 min, 1a (100 mg, 0.36 mmol) was added and
the resulting yellow solution was stirred at 458C for 5 h. The reaction
was quenched using water (20 mL) and the pH was adjusted to pH 5
using 1n HCl. The mixture was extracted using dichloromethane
(10 mL ꢀ 3). The combined organic layers were washed with brine
(10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to
give the crude product, which was further purified using column
chromatography on silica gel (petroleum ether/ethyl acetate = 10:1)
By using the optimized reaction conditions, various 3-(1-
alkynyl)chromones 1 were treated with 2a to extend the scope
of this tandem reaction. Good to excellent yields were
obtained when R1 was an aromatic group on the acetylene
moiety (Table 1, entries 1–3). It was noted that an electron-
donating group was beneficial to the domino process. When
R1 was an aliphatic chain, the reactions gave a modest yield
(Table 1, entries 4 and 5). Substitution with a sterically
hindering group (tert-butyl) afforded the intermediate 7 f,
which did not readily transfer to the final product (Table 1,
1
to afford 3a as a white solid (m.p. 265–2678C). H NMR (300 MHz,
CDCl3): d = 11.73 (s, 1H), 8.96 (s, 1H), 8.30 (dd, J = 7.8 Hz, J =
1.8 Hz, 1H), 7.68–7.62 (m, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.36 (t, J =
7.8 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 4.03 (s,
3H), 3.90 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d = 176.27,
170.37, 163.15, 159.30, 157.48, 156.08, 134.80, 131.94, 129.80, 126.62,
Angew. Chem. Int. Ed. 2009, 48, 6520 –6523
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6521
Zhao, Lizhi
