Y.-L. Zhang, Y.-Q. Wang / Tetrahedron Letters 55 (2014) 3255–3258
3257
wed the reaction such that conversion was only 12% after 72 h.
Raising the reaction temperature increased the yield to 90% but
the enantioselectivity decreased dramatically to 23% ee (entry 8).
Varying the solvent could not enhance reactivity or enantioselec-
tivity (entries 9–12). Given that adding organic acid could acceler-
ate the formation of the iminium-ion intermediate,17 we tested a
series of organic acids in our cyclization system. As expected, the
oxa-Michael reaction of 20-hydroxychalcone was much faster in
the presence of a catalytic amount of various benzoic acids (entries
13–17). The best result was obtained by adding 4-chlorobenzoic
acid, which gave the desired flavanone in 68% yield with 96% ee
(entry 14). Gratifyingly, the enantioselectivity was maintained
and the yield remained mostly unchanged with decreased catalyst
amount to 10 mol %, albeit a little longer time was needed (entry
18). We were intrigued to find that 2-aminopyridine derivatives
could not substitute for 3a to catalyze the oxa-Michael reaction
of 20-hydroxychalcone under the same reaction conditions (entries
19 and 20). We expected 2-aminopyridine derivatives to work
because they are excellent H-bond catalysts reported previously.18
Under the optimized reaction conditions, a variety of represen-
tative 20-hydroxychalcones were investigated (Scheme 3). Various
substituted 20-hydroxychalcones reacted smoothly in moderate to
good yield with high enantioselectivity. Both electron-withdraw-
ing and electron-donating groups were tolerated on the right aryl
ring, yielding the desired products in 55–80% yield and 84–96%
ee (Scheme 3, 2a–2h). In particular, 20-hydroxychalcone bearing
naphthalene as the right aryl ring reacted smoothly to afford the
corresponding flavanone in 67% yield with 99% ee (Scheme 3, 2i).
We also examined the effect of electronic and structural varia-
tions on the left aryl ring. Previous study, in which chiral flavanon-
es were generated from chalcones activated by C-2 tert-butyl ester
(Scheme 1a), reported that electron-poor substituents on the phe-
nol moiety dramatically decreased the enantioselectivity of the
oxa-Michael reaction11b; for example, flavanone substituted with
chloride (2j) was produced with only 40% ee.11b We were pleased
to find that adding Cl to the phenol moiety created a suitable
Michael donor for our cyclization reaction; the substrate generated
the corresponding product 2j in good yield with 93% ee (Scheme 3,
2j). Placing an electron-withdrawing 40-TsO group on the phenol
moiety also afforded the desired flavanone in 63% yield with 83%
ee (Scheme 3, 2k).
20-Hydroxy-naphthol chalcones were challenging substrates for
the oxa-Michael reaction in the literature, for instance, flavanone
(2l) was obtained with 46% ee.15a Pleasingly, this substrate could
be converted into the desired flavanone in good yield with high
enantioselectivity by our approach (e.g., 2l 82% yield and 95% ee,
Scheme 3). Our organocatalytic process was readily scaled up to
1 mmol without loss of reactivity or enantioselectivity (Scheme 3,
2a). In addition, the catalyst was conveniently recovered using an
acid–base conversion procedure. The recovered catalyst could pro-
mote the biomimetic cyclization of 20-hydroxychalcone in good
yield albeit with slightly decreased enantioselectivity (Scheme 3,
2f). These reaction conditions tolerated certain functional substit-
uents, including F, Cl, Br, and TsO, which can subsequently be
transformed into other functionalities.
In summary, we have designed and synthesized a new family of
organocatalysts based on aminoquinoline and pyrrolidine. The
organocatalysts can promote enantioselective oxa-Michael reac-
tion of 20-hydroxychalcones to afford flavanones in good yield with
high enantioselectivity. The simple and straightforward biomi-
metic cyclization is performed under mild conditions and it toler-
ates moisture and air. This approach provides a facile and efficient
access to chiral flavanones. Studies of the mechanism and applica-
tions of this catalytic system are in progress.
This high enantioselectivity is probably due to good arene
ing between substrate and catalyst.
p-stack-
Cat. 3a (10 mol%l)
OH
O
H
R2
4-chlorobenzoic acid
(10 mol%)
O
O
R1
R1
R2
toluene, RT
2
1
OMe
Cl
H
H
H
O
O
O
O
Acknowledgments
O
We thank National Natural Science Foundation of China (NSFC-
20872183, 20972126, 21272185), the Program for New Century
Excellent Talents in University of the Ministry of Education China
(NCET-10-0937), and Education Department of Shaanxi Provincial
Government (09JK776).
O
93% ee (56%)b
96% ee (65%)a
2c
2a
2d
2b 85% ee (64%)
H
O
H
H
O
O
F
Cl
Br
O
O
O
92% ee (69%)c
90% ee (66%)
2f
2e
90% ee (64%)
90% ee (80%)
Supplementary data
H
O
H
O
H
O
Supplementary data (Experiment details, copies of HPLC, 1H and
13C NMR spectra for products. This material is available free of
charge via the Internet at doi.) associated with this article can be
OMe
Br
O
O
O
2i
99% ee (67%)
2h 90% ee (60%)
2g 90% ee (55%)
OMe
H
O
H
O
H
O
TsO
References and notes
Cl
O
O
O
83% ee (63%)d
2j
93 % ee (67%)
2k
2l
95% ee (82%)
Scheme 3. Substrate scope. General reaction conditions: 1 (0.1 mmol), catalyst 3a
(10 mol %) and 4-chlorobenzoic acid (10 mol %) in 0.3 mL toluene at rt. Values for ee
were determined by HPLC using a chiral stationary phase (see the Supporting
information). Yields of isolated products are shown in parentheses. The absolute
configuration of 2a–2c and 2i were determined as S by comparison of optical
rotation to literature values (see the Supporting information details). a1 mmol
substrate was used. b2,4-Dichlorobenzoic acid was used as additive, 20 mol % 3a
was used. cRecovered catalyst 3a was used. dThe reaction was performed at 50 °C
without additive.