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C.-Q. Wang et al. / Chinese Chemical Letters 26 (2015) 793–796
increasing amount of iodine and a prolonged reaction time. This
side reaction was used to design the following synthetic route.
Intermediate 11 were synthesized by the known procedure
[21,22]. In the presence of iodine/pyridine, the cyclization of
intermediate 11 and demethylation yielded flavone compound 7
with a hydroxy group at position 5 of ring A with 73% yield. In the
presence of benzyl chloride, intermediate 7 gave the flavone benzyl
ether compound 2, in which the hydroxyl groups on the A ring is
benzylated. Intermediate 2 underwent a rearrangement reaction
under microwave conditions in the presence of methylsulfonic
acid to yield rearrangement products and debenzylated product 7,
similar to the reaction above. Surprisingly, the benzyl group in the
reaction was not rearranged to the position ortho of the original
benzyloxy group of ring A (position 6 of compound 2). The
structural characterization confirmed that the benzyl group was
rearranged to the position 60 of compound 2 and yielded a
benzylated product 5. The yield of all of the rearrangement
products declined (26%) versus compound 1 (64%). Finally, the
Fig. 1. Basic flavone skeleton and benzyl-substituted flavone compounds.
it significantly shortened the reaction time to less than 30 min. The
detailed synthetic route is shown in Scheme 1. Detail materials and
methods and the spectra of the products were listed in Supporting
information.
First, to introduce the benzyl group to ring B of luteolin
(Scheme 1, Route I), flavone benzyl ethers that benzylate the
hydroxyl group on the B ring were needed. Intermediate 10 were
synthesized by the known procedure [21,22]. In the presence of
iodine/pyridine, the intermediate 10 underwent cyclization to give
a flavone benzyl ether compound 1 with 72% yield, in which the
hydroxyl groups on the B ring were benzylated. Using microwave,
the intermediate 1 underwent a rearrangement reaction in the
presence of methylsulfonic acid. This reaction yielded rearrange-
ment products and debenzylated product 6. Notably, the reaction
produced two rearrangement products. Through structural char-
acterization, the benzyl group was found to rearrange to the ortho
position of the original benzyloxy group (position 50 of compound
1) to give a benzylated product 3. Furthermore, it also rearranged
to the meta position (position 60 of compound 1) to yield the
benzylated product 4. In addition, the proportions of the two
products were equivalent, and the yields were 34% and 30%,
respectively. Finally, intermediates 3 and 4 underwent demethyl-
ation via boron tribromide to obtain the target compounds 30-
benzyl luteolin 8 and 20-benzyl luteolin 9 with 34% and 30% yields.
Although the yield of the single reaction via this route was not high,
the intermediate 6 could be re-used to improve the overall yield of
the multiple reactions.
demethylation of intermediate
compound 20-benzyl luteolin
tribromide. Similarly, the cyclic utilization of intermediate 7 could
enhance the overall yield through multiple reactions down this
route.
5
yielded the same target
9
in the presence of boron
3. Results and discussion
From the total synthesis of benzyl-substituted flavone deriva-
tives, complicated regioselectivity during the rearrangement of the
benzyl group in flavone benzyl ether compounds was observed.
The benzyl group could be rearranged not only to the position ortho
of the original benzyloxy group, but also to the meta position (the
benzyl group of compound 1 rearranged from the 40 to the 50 and 60
positions). Rearrangement to the flavone B ring from the flavone A
ring is also possible (the benzyl group of compound 2 rearranged
from position 5 to position 60). This is different from the
regioselectivities previously reported for simple aromatic com-
pounds and flavanone compounds, in which the rearrangement of
a benzyl group mainly occurred on the ortho and para positions,
and ortho rearrangement dominated [10,12]. This may be because
previous systems were relatively simple, and the flavone
compound system with four substituted groups used here is
relatively complicated. This gives a relatively complicated regios-
electivity during the rearrangement of the benzyl group.
Second, a benzyl group was tried to be introduced to the ring A
of luteolin (Scheme 1, Route II). Similarly, flavone benzyl ethers, in
which the hydroxyl groups on the A ring was benzylated, were
obtained. In the preliminary study, the cyclization reaction in the
presence of iodine/pyridine was found to generate a byproduct
that was demethylated at position 5 of the flavone backbone. In
addition, it will gradually become the main product with an
A reaction mechanism for the acidic rearrangement of the
benzyl group in aromatic benzyl ether compounds was proposed
by some researchers, based the observation of the intermolecular
benzylated product [10,12]. According to this reaction mechanism
(Scheme 2), the flavone benzyl ethers were first protonated under
Scheme 1. Synthetic route I and II of benzyl-substituted flavone compounds. Reagents and conditions: a: DMS, K2CO3, acetone, r.t.; b: benzyl chloride, K2CO3, DMF, reflux; c:
50% KOH, CH3OH, r.t.; d: I2, pyridine, reflux; e: MSA, CHCl3, microwave; f: BBr3, DCM, r.t.