A concise synthesis of 3-aroylflavones via Lewis base 9-azajulolidine- catalyzed tandem acyl transfer-cyclization

Article abstract of DOI:10.1039/c2cc37015h

Lewis base-catalyzed tandem acyl transfer-cyclization of acylated o-alkynoylphenols leading to 3-aroylflavones was developed. 9-Azajulolidine smoothly promoted the reaction of the aroyl derivatives at ambient temperature, and the structure-diversed synthesis of 3-aroylflavones with distinct substituents was achieved in moderate to excellent yields.

Full text of DOI:10.1039/c2cc37015h

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COMMUNICATION
A concise synthesis of 3-aroylflavones via Lewis base
9-azajulolidine-catalyzed tandem acyl transfer–cyclizationw
Masahito Yoshida, Koya Saito, Yuta Fujino and Takayuki Doi*
Received 27th September 2012, Accepted 23rd October 2012
DOI: 10.1039/c2cc37015h
Lewis base-catalyzed tandem acyl transfer–cyclization of acylated
o-alkynoylphenols leading to 3-aroylflavones was developed.
9-Azajulolidine smoothly promoted the reaction of the aroyl
derivatives at ambient temperature, and the structure-diversed
synthesis of 3-aroylflavones with distinct substituents was achieved
in moderate to excellent yields.
cyclization of o-alkynoylphenols could be employed.10
We postulated that allenolate 3 would be generated after 1,4-
addition of Lewis base X such as DMAP to 2, and then
attack of the aroyl group on the phenol, similar to the
Baker–Venkataraman rearrangement, to afford the acylated
enone 4. Acylated enone 4 should be a good Michael acceptor,
and therefore undergo intramolecular cyclization of the resulting
phenoxide to the b-carbon, followed by elimination of the Lewis
base to provide 3-aroylflavones 1. The above synthesis could
efficiently supply 3-aroylflavones with distinct substituents
(Ar1 a Ar2), whereas the conventional synthesis via the
Baker–Venkataraman rearrangement mostly provides products
with the same aryl groups (Ar1 = Ar2). The integrated reaction
sequence would also be performed with a catalytic amount of
Lewis base, and therefore could be an efficient and useful
method for the synthesis of 3-aroylflavones (Scheme 1).11
The reaction conditions were first investigated using benzoate
2a, and the results are shown in Table 1. According to our
previous report,10 the reaction was attempted in the presence of
10 mol% DMAP in DMF and proceeded at 30 1C for 42 h to
afford a mixture of the desired 1a (77% yield) and flavone 5a in
a ratio of 86 : 14 (entry 1). Treatment with 30 mol% DMAP
consumed 2a in 22 h to provide 1a in 79% yield (entry 2). The
compound 4-pyrrolidinopyridine (PPY), which has been
reported as a good catalyst for the acylation of tert-alcohols,12
also promoted the acyl transfer–cyclization of 2a. However, the
yield of 1a was found to be 82%, which was similar to that
obtained using DMAP (entry 3). Therefore, in order to improve
the yield of 3-aroylflavone 1a, 9-azajulolidine (9-AJ),13 which is
known as a highly active catalyst for acylations, was utilized in
Among the numerous types of heterocycles, the g-benzopyrone
skeleton is often found in both natural and synthetic biologically
active substances and has been recognized as a preferred
structure in the discovery of novel drug candidates.1 Although
many types of g-benzopyrone-containing natural products have
been isolated from nature over the last decade, flavones, one of
the main sub-classes of dietary flavonoids, exhibit a wide variety
of biological activity.2 For example, nobiletin enhances PKA-
mediated phosphorylation of GluR1,3 and baicalin promotes
osteoblastic differentiation via the activation of the Wnt/
b-catenin signalling pathway.4 Of the numerous flavone derivatives
that have been isolated from natural sources or synthesized,
3-aroylflavone derivatives 1 may be an interesting scaffold for drug
discovery. It has been reported that 3-aroylflavones exhibit several
types of biological activity such as antibacterial, antifungal, and
antitubulin.5 Although the 3-aroylflavone derivatives can be pre-
pared as an over-reaction product in the conventional synthesis of
flavones from 2-hydroxyacetophenones by Baker–Venkataraman
rearrangement,6–8 only limited derivatives
1 =
(Ar1 Ar2)
were obtained.9 Therefore, a novel synthetic method producing
3-aroylflavones with distinct substituents (Ar1 a Ar2) would be
useful for the structural diversity of flavonoid derivatives. Herein,
we report the concise and structure-diversed synthesis of 3-aroyl-
flavone derivatives via a Lewis base 9-azajulolidine-catalyzed
sequential acyl transfer–cyclization under ambient conditions.
To achieve the synthesis of the desired 3-aroylflavones 1 from
acylated o-alkynoylphenols 2, we considered that our reported
4-(dimethylamino)pyridine (DMAP)-catalyzed regioselective
Graduate School of Pharmaceutical Sciences, Tohoku University,
6-3 Aza-Aoba, Aramaki, Aoba-ku Sendai 980-8578, Japan.
E-mail: doi_taka@mail.pharm.tohoku.ac.jp; Fax: +81-22-795-6864;
Tel: +81-22-795-6865
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data of all products, 1H and 13C NMR
spectra, as well as HPLC UV traces of cross-over experiments and
crystal structure of 1h. CCDC 897539. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc37015h
Scheme 1 Plausible reaction mechanism for the tandem acyl transfer
and cyclization.
c
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Table 1 Investigation of the reaction conditions for the tandem acyl
transfer–cyclization
Table 2 Scope and limitation of the 9-AJ-catalyzed tandem acyl
transfer–cyclization of 2
Catalyst
Entry (mol%)
Ratio of
T/1C t/h 1a : 5aa
Yieldb
(%)
Solvent
2
1b (%)
1
2
3
4
5
6
7
DMAP (10) DMF
DMAP (30) DMF
30
30
30
30
30
42
22 >95 : 5
21 93 : 7
6 >95 : 5
86 : 14
77
79
82
88
47
84
50
Entry R1
R2
R3
R4
Ar
t/h
(1 : 5)c
PPY (30)
9-AJ (30)
9-AJ (30)
9-AJ (30)
9-AJ (30)
DMF
DMF
Toluene
Toluene 100
THF 30
1
2b
OMe
2c
Cl
2d
Br
2e
CN
2f
22
1b : 63
(71 : 29)
1c : 92
(>95 : 5)
1d : 96
(>95 : 5)
1e : 97
(>95 : 5)
1f : 90
(>95 : 5)
1g : 96
(>95 : 5)
1h : 98
(>95 : 5)
1i : 73
(76 : 24)
1j : 81
(81 : 19)
1k : 70d
(89 : 11)
1l : 85
(92 : 8)
1m : 94
(>95 : 5)
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
90
69 : 31
88 : 12
59 : 41
2
5
3
24
55
H
H
3
a
The ratio of 1a and 5a was determined from the crude 1H NMR
H
H
b
spectrum. Isolated yield of 1a.
4
7
H
H
5
4
H
OMe
Cl
Br
H
H
6
2g
H
3
this reaction. The reaction proceeded smoothly for 6 h in the
presence of 30 mol% 9-AJ to afford the desired 1a in 88% yield.
The ratio of 3-aroylflavone 1a and flavone 5a also increased to
>95 : 5 (entry 4). The 1,4-addition of 9-AJ to 2a would be
accelerated compared to that of DMAP and PPY forming the
corresponding 1a. This is because, as Steglich et al. reported,
both the rigid conformation and the inductive electron-donating
effect of an alkyl group in the meta position might have a similar
effect on the corresponding 4-(dialkylamino)pyridine and cause
an increase in the electron density at the pyridine nitrogen atom
of 9-AJ.13 The existence of any solvent effects on the 9-AJ-
catalyzed acyl transfer–cyclization of 2a was also investigated.
The reaction in non-polar toluene proceeded at 100 1C, forming
1a in 84% yield, whereas the reaction at 30 1C gave 1a in 47%
yield (entries 5 and 6). The use of the aprotic, less polar solvent
tetrahydrofuran gave poor results (entry 7), because the
1,4-addition of 9-AJ to the a,b-unsaturated ketone should be
rather slower in less polar media.
H
7
2h
H
3
H
8
2i
16
4
H
OMe
Cl
H
9
2j
H
H
10
11
12
2k
H
2l
H
2m
H
5
H
OMe Ph
14
H
H
H
H
p-OMePh
p-ClPh
2.5
H
H
a
b
30 mol% 9-azajulolidine was used. Isolated yield. The ratio of 1
and 5 was determined from the crude 1H NMR spectrum. Unidenti-
fied product was obtained in 5% yield.
c
d
1k. However, an unidentified product was also obtained in 5%
yield (entry 10).15 The substituents on the aromatic ring of the
alkyne were also observed to affect the transformation. The
reaction of 2l possessing a p-methoxyphenyl group was complete
in 14 h, yielding 1l, because the addition of 9-AJ to the a,
b-unsaturated ketone occurred slowly due to the electron-donating
effect of the p-methoxyphenyl group. On the other hand, substrate
2m was smoothly consumed in 2.5 h to provide 1m in 94% yield
because 1,4-addition of 9-AJ proceeded readily due to the electron-
withdrawing effect of the p-chlorophenyl group. Finally, similar to
the reaction of benzoate derivatives 2a–m, naphthoate 2n and
furoate 2o were tolerated in this reaction and the desired products
1n and 1o were obtained in moderate yields (Scheme 2).16
With the optimal conditions in hand, the scope of the 9-AJ-
catalyzed reaction was investigated, and the results are depicted
in Table 2. The reaction of 2b possessing an electron-donating
methoxy group at the R1 position slowly proceeded and
3-aroylflavone 1b was afforded concomitantly with flavone 5a
in moderate yield (entry 1). The electron-donating group at the
R1 position strongly decreased the electrophilicity of the carbonyl
moiety in the aroyl group, and therefore the protonation of the
resulting enolate occurred concomitantly with nucleophilic attack
at the aroyl group. On the other hand, substrates 2c–e with
electron-withdrawing groups at the R1 position were smoothly
consumed, and the corresponding 1c–e were preferably obtained
in high yields due to the increased electrophilicity (entries 2–4).
Transfer of the aroyl group in 2f–h, followed by cyclization of the
resulting phenol provided 1f–h in excellent yields, regardless of the
substituents at the R2 position.14 In addition, 3-aroylflavone 1j
containing a Cl substituent at the R3 position was obtained from
2j in 81% yield, whereas the reaction of 2i containing a methoxy
group at the same position proceeded slowly to provide 1i in 73%
yield due to the decrease in the electrophilicity of the carbonyl
group (entries 8 and 9). Substrate 2k possessing a methoxy group
at the R4 position was smoothly consumed within 5 h to afford
Next, the 9-AJ-catalyzed reaction of 3-bromonbenzoate 2h
in the presence of an excess amount of D2O was examined as
part of a mechanistic study of the reaction. Substrate 2h was
smoothly consumed, and it was observed that 3-aroylflavone
Scheme 2 9-AJ-catalyzed tandem acyl transfer–cyclization of 2n
and 2o.
c
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Network Joint Research Center for Materials and Devices,
No. 2011341.
Notes and references
1 (a) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev.,
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2 (a) Ø. M. Andersen and K. R. Markham, Flavonoids: Chemistry,
Biochemistry and Applications CRC, Boca Raton, FL, 2006;
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25, 555; (c) A. Crozier, I. B. Jaganath and M. N. Clifford, Nat.
Prod. Rep., 2009, 26, 1001.
Scheme 3 9-AJ-catalyzed reaction of 2h in the presence of D2O.
3 K. Matsuzaki, K. Miyazaki, S. Sakai, H. Yawo, N. Nakata,
S. Moriguchi, K. Fukunaga, A. Yokosuka, Y. Sashida,
Y. Minami, T. Yamakuni and Y. Ohizumi, Eur. J. Pharmacol.,
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4 A. J. Y. Guo, R. C. Y. Choi, A. W. H. Cheung, V. P. Chem,
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5 J. Quinti, C. Roullier, S. Thoret and G. Lewin, Tetrahedron, 2006,
62, 4038.
6 (a) W. Baker, J. Chem. Soc., 1933, 1381; (b) H. S. Mahal and
K. Venkataraman, J. Chem. Soc., 1934, 1767.
Scheme 4 Cross-over experiment with an external phenol ester 7.
7 Flavone synthesis via Baker–Venkataraman rearrangement, see;
(a) M. Iinuma, T. Tanaka, M. Mizuno and Z.-D. Min, Chem.
Pharm. Bull., 1985, 33, 3982; (b) T. Horie, K. Shibata,
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B. Westermann, M. Abbas and I. Green, Tetrahedron: Asymmetry,
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M. Inai, H. Nukaya, T. Wakimoto and T. Kan, Org. Lett., 2009,
11, 2233; (e) M. Ono, R. Ikeoka, H. Watanabe, H. Kimura,
T. Fuchigami, M. Haratake, H. Saji and M. Nakayama, Bioorg.
Med. Chem. Lett., 2010, 20, 5743; (f) T. Asakawa, A. Hiza,
M. Nakayama, M. Inai, D. Oyama, H. Koide, K. Shimizu,
T. Wakimoto, N. Harada, H. Tsukada, N. Oku and T. Kan,
Chem. Commun., 2011, 47, 2868; (g) Y. Yu, Y. Hu, W. Shao,
J. Huang, Y. Zuo, Y. Huo, L. An, J. Du and X. Bu, Eur. J. Org.
Chem., 2011, 4551.
8 (a) F. M. Hauser and R. P. Rhee, J. Am. Chem. Soc., 1979,
101, 1628; (b) B. J. D. Wright, J. Hartung, F. Peng, R. Van de
Water, H. Liu, Q.-H. Tan, T.-C. Chou and S. Danishefsky, J. Am.
Chem. Soc., 2008, 130, 16786.
9 (a) A. K. Ganguly, S. Kaur, P. K. Mahata, D. Biswas,
B. N. Pramanik and T. M. Chan, Tetrahedron Lett., 2005,
46, 4119; (b) A. K. Ganguly, P. K. Mahata and D. Biswas,
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A. M. S. Silva and J. A. S. Cavaleiro, Synlett, 2007, 1897;
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1h was obtained in 47% yield along with deuterated flavone 6
(37%) (Scheme 3).
Furthermore, cross-over experiments for the 9-AJ-catalyzed
reaction with an external phenol ester 7 were conducted, and
the ratio of the products was determined by HPLC with a peak
area (UV) at 310 nm (Scheme 4). The reaction of 2h in the
presence of one equivalent of phenol ester 7 was performed in
the polar solvent DMF at 30 1C to provide the corresponding
1h and the cross-over product 1c in a ratio of 85 : 15. On the
other hand, when the reaction was carried out in the non-polar
solvent toluene at 100 1C, the desired 1h was exclusively
observed by HPLC analysis (1h : 1c = >99 : 1).17 These
results suggest that the nucleophilicity of the 9-AJ adduct 3
was so increased by the effect of solvation in DMF that inter-
molecular addition proceeded. Based on the above observations,
it can be concluded that allenolate 3 is initially generated by
means of the 1,4-addition of 9-AJ to substrate 2, and that the
intramolecular rearrangement of the aroyl group is favorable
compared to intermolecular addition in the 9-AJ-catalyzed reaction.
In summary, a novel concise synthesis of 3-aroylflavones 1 via
a Lewis base-catalyzed tandem acyl transfer and cyclization
reaction has been developed. The compound 9-azajulolidine
(9-AJ) is a more effective catalyst rather than DMAP or PPY
for efficiently promoting the acyl transfer of the aroyl group in 2
and cyclization of the resulting phenol to provide a 3-aroyl-
flavone 1 in moderate to excellent yields. Substrates 2 can be
prepared from three components: benzaldehydes, arylacetylenes
and acid chlorides. Therefore, this new method could become a
convergent approach to biologically active 3-aroylflavones.
Mechanistic studies suggest that the reaction proceeds via the
corresponding allenolate 3 through the 1,4-addition of 9-AJ and
transfer of the aroyl group is favorably performed in an intra-
molecular fashion to afford the corresponding 3-aroyflavone
derivatives. The biological evaluation of synthetic 3-aroylflavones
and the application of this method to the synthesis of naturally
occurring flavonoids are currently under investigation.
10 M. Yoshida, Y. Fujino, K. Saito and T. Doi, Tetrahedron, 2011,
67, 9993.
11 (a) S. Suga, D. Yamada and J. Yoshida, Chem. Lett., 2010, 39, 404;
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12 A. Hassner, L. R. Krepski and V. Alexanian, Tetrahedron, 1978,
34, 2069.
13 M. R. Heinrich, H. S. Klisa, H. Mayr, W. Steglich and H. Zipse,
Angew. Chem., Int. Ed., 2003, 42, 4826.
14 The structure of 3-aroylflavone was confirmed by X-ray
crystallographic analysis of 1h; CCDC 897539 (1h).
15 According to our knowledge, we speculated that the unidentified
product could be
a 5-exo cyclized product because 5-exo
cyclization of the alkynoylphenol containing a methoxy group at
the ortho-position of the carbonyl group was partially observed,
see ref. 10.
16 Acetate derivative 2p was also investigated, however the mixture of
1p and 5 was obtained in the ratio of 53 : 47, see ESIw.
17 The cross-over experiments of 2h with 7 in toluene at 30 1C also
predominantly provided 1h (1h : 1c = >99 : 1, see ESIw), thus the
mode of acyl transfer in the 9-AJ-catalyzed reaction would depend
on the polarity of the solvent.
We thank Prof. Dr Katsuhiko Tomooka and Dr Kazunobu
Igawa for the fruitful discussion. This work was supported by
a Grant-in-Aid for Scientific Research on Innovative Areas
(No. 2105), and by the Cooperative Research Program of
c
11798 Chem. Commun., 2012, 48, 11796–11798
This journal is The Royal Society of Chemistry 2012