An efficient synthesis of aurone derivatives by the tributylphosphine-catalyzed regioselective cyclization of o-alkynoylphenols

Article abstract of DOI:10.1246/cl.140910

An organocatalytic regioselective synthes is of aurones from o-alkynoylphenols was achieved. A catalytic amount of tributylphosphine select ively induced the 5-exo cyclization of o-alkynoylphenols under ambient conditions leading to aurone derivatives in high to excellent yields.

Full text of DOI:10.1246/cl.140910

Received: September 30, 2014 | Accepted: November 4, 2014 | Web Released: November 8, 2014
CL-140910
An Efficient Synthesis of Aurone Derivatives by the Tributylphosphine-catalyzed
Regioselective Cyclization of o-Alkynoylphenols
Koya Saito, Masahito Yoshida, and Takayuki Doi*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578
(E-mail: doi_taka@mail.pharm.tohoku.ac.jp)
An organocatalytic regioselective synthesis of aurones from
o-alkynoylphenols was achieved. A catalytic amount of tri-
butylphosphine selectively induced the 5-exo cyclization of o-
alkynoylphenols under ambient conditions leading to aurone
derivatives in high to excellent yields.
produced aurone (1a) in a ratio of 76:24.1b Therefore, we further
investigated PBu3-catalyzed cyclization in a protic media to
achieve the regioselective 5-exo cyclization of o-alkynoyl-
phenols 3.
We postulated that 3 would undergo 1,4-addition of a Lewis
base, such as PBu3, leading to allenol 4 in a protic medium and
that 5-exo cyclization would provide aurone 1. On the other
hand, if the isomerization of 4 to enone 5 occurred, it would be
readily converted to flavone 2 via 6-endo cyclization.1 Thus, the
rapid 5-exo cyclization of 4 to 1 is the key to achieve this
regioselective synthesis of aurones 1 (Figure 2).
During initial investigation of the reaction conditions for the
cyclization of 3a the results are summarized in Table 1. The
reaction in the presence of 10 mol % of 9-azajulolidine (9-AJ)8
proceeded in EtOH at 30 °C leading to a mixture of 1a and 2a
in a ratio of 28:72 (Entry 1).9 Alternatively, the regioselective
cyclization of 3a was smoothly performed in the presence of
10 mol % of PBu3 to provide the 5-exo cyclized aurone (1a) as
a single Z-isomer in 94% yield with >95:5 regioselectivity
(Entry 2). Notably, a catalytic amount of PBu3 was reduced to
2.5 mol % without affecting the yield and regioselectivity of 1a
(Entries 3 and 4). In addition, it was found that the afforded
aurone (1) was not converted to the thermodynamically favored
flavone (2) under the reaction conditions, thus it is conceivable
that this reaction would be irreversible. PPh3 was also effective
in the regioselective cyclization of 3a leading to 1a (88%,
1a:2a = >95:5, Entry 5), whereas tricyclohexylphosphine
(PCy3) lost both catalytic activity and regioselectivity due to
Aurones (1, Figure 1), a main subclass of flavonoids, are
often found in vegetables, fruits, and flowers, and are known to
exhibit unique and beneficial biological activities such as
anticancer, antimalarial, and antimicrobial effects.2 Aurone (1)
is comprised of a benzofuranone skeleton with an aryl moiety
connected by a carbon-carbon double bond. Most naturally
occurring aurones are isolated as hydroxylated, methoxylated,
or glycosylated derivatives. To date, several synthetic methods
for aurone derivatives have been reported, such as the aldol or
Knoevenagel reaction of benzofuranone with an aldehyde,3
oxidative cyclization of 2-hydroxychalcone,4 and Suzuki-
Miyaura coupling of (Z)-2-(bromomethylene)benzofuranone
derivative with an aryl boronic acid.5 In particular, the 5-exo
cyclization of o-alkynoylphenols 3 is a convenient method for
the preparation of aurone derivatives 1. However, the cyclization
of 3 is often problematic as it often provides a mixture of 5-exo
cyclized aurones 1 and 6-endo cyclized flavones 2 (Figure 1).6
To improve the regioselectivity of the cyclization of o-
alkynoylphenols 3, the metal-catalyzed 5-exo cyclization of 3
was recently developed and utilized in the synthesis of aurone
derivatives 1.7 On the other hand, we recently reported the
regioselective 6-endo cyclization of 3, which proceeded in the
presence of TfOH or a catalytic amount of (4-dimethylamino)-
pyridine (DMAP) leading to flavones 2.1 For example, the
reaction of 3a performed in DMF selectively afforded flavone
(2a) (1a:2a = 5:>95), whereas in EtOH it afforded a certain
amount of aurone (1a) (1a:2a = 13:87). Intriguingly, the cy-
clization of 3a in the presence of PBu3 in DMF predominantly
R
R'
OH
O
3
X: Lewis base
R
R
5-exo
cyclization
O– X+
R'
R
R
R'
R
O
R'
OH
O
R'
O
R'
O
+
HO
O
O
Allenol 4
Aurone 1
O
Aurone 1
Flavone 2
o-Alkynoylphenol 3
(5-exo cyclized product) (6-endo cyclized product)
R
R
X+
O–
Regioselectivity
6-endo
cyclization R'
Conditions
1a (R = R' = H) : 2a (R = R' = H)
R'
Substrate
O
K2CO3/EtOH
77 : 23
5 : >95
13 : 87
76 : 24
3a (R = R' = H)
10 mol% DMAP/DMF
10 mol% DMAP/EtOH
10 mol% PBu3/DMF
3a
3a
3a
H
O
O
Enone 5
Flavone 2
Figure 1. Previous reports showing, regioselectivity in the
cyclization of o-alkynoylphenol 3a.1b
Figure 2. A plausible mechanism of 5-exo cyclization of
o-alkynoylphenol 3 leading to aurone 1.
Chem. Lett. 2015, 44, 141–143 | doi:10.1246/cl.140910
© 2015 The Chemical Society of Japan | 141

its steric hindrance (1a:2a = 70:30, Entry 6).10 When 3a was
placed in EtOH in the absence of a catalyst, on the other hand,
it was slowly converted to a mixture of 1a and 2a in 18 h
(Entry 7). Thus it should be noted that the addition of PBu3 is
crucial for the regioselective cyclization of 3a to provide the
5-exo cyclized aurone (1a).
With the optimized reaction conditions in hand, the scope of
the substrates was investigated (Table 2). The substrate 3b,
possessing an electron-withdrawing chloride atom on the B-ring,
was smoothly consumed within 5 min and the corresponding
aurone 1b was regioselectively afforded in 91% yield (Entry 1).
The reaction of 3c containing a methoxy group at the para-
position on the B-ring, however, slowly proceeded to yield 1c
(99%). This was probably because the 1,4-addition of PBu3 to 3c
was slower due to a decrease in electrophilicity of an ynone
moiety by the electron-donating methoxy group on the B-ring
(Entry 2). The reaction of 3d smoothly proceeded to 1d in 95%
yield (Entry 3), thus the methoxy group at the meta-position on
the B-ring did not affect the cyclization. In addition, it was found
that a number of methoxy groups on the B-ring in 3e and 3f did
not affect the regioselectivity, and the corresponding aurones 1e
and 1f were provided in 93% and 88% yields, respectively
(Entries 4 and 5). The effect of a substituent on the A-ring
was also investigated. The reaction of 3g (R4 = OMe) was
completed within 5 min to afford 1g in 93% yield. This was
due to the increased nucleophilicity of the phenol moiety from
the resonance effect of an electron-donating methoxy group
(Entry 6). Whereas, it took 15 min to complete the reaction of
3h containing a methoxy group at R5 to afford 1h in 98%
yield (Entry 7). The 5-exo cyclization of 3k and 3l was also
selectively performed to afford 1k and 1l in good yields
(R6 = OMe in Entry 10 and R7 = OMe in Entry 11). However,
substrates 3i and 3j possessing a halogen atom (R6 = Cl for 3i,
Br for 3j) were slowly consumed, leading to 1i (59%) and 1j
(58%) with poor regioselectivities (1i:2i = 62:38 in Entry 8 and
1j:2j = 59:41 in Entry 9). It is conceivable that the isomer-
ization of the allenol 4 to the enone 5 occurred partially due to
the lower nucleophilicity of the phenol moiety as a result of
the electron-withdrawing halogen atom on the A-ring (Figure 2),
causing 6-endo cyclized products 2i and 2j to also be formed.
We next investigated the PBu3-catalyzed reaction of 3a in
ethanol-d6 as a mechanistic study of the reaction (Scheme 1).
Substrate 3a was smoothly converted into the deuterated aurone
Table 1. Investigation results of the reaction conditions for
5-exo cyclization of o-alkynoylphenol 3a
OH
O
O
+
EtOH, 30 °C
O
O
O
Aurone (1a)
(5-exo cyclized product)
Flavone (2a)
(6-endo cyclized product)
o-Alkynoylphenol 3a
Ratio of Yield of 1ab
Entry Catalyst (mol %) Time
1a:2aa
/%
1
2
3
4
5
6
7c
9-AJ (10)
PBu3 (10)
PBu3 (5)
PBu3 (2.5)
PPh3 (10)
PCy3 (10)
®
3 h
28:72
>95:5
>95:5
>95:5
26
94
94
92
88
55
14
5 min
5 min
5 min
30 min >95:5
2 h
PBu3
O
O
2.5 mol% PBu3
3a
ethanol-d6
D (H)
DO
O
70:30
50:50
6
7
(D:H = 93:7)
18 h
1
b
aThe ratio was determined by crude H NMR. Isolated yield.
cThe substrate 3a was recovered in 63% yield.
Scheme 1. PBu3-catalyzed 5-exo cyclization in deuterated
ethanol.
Table 2. Scope and limitation on regioselective synthesis of 1 via PBu3-catalyzed 5-exo cyclization of 3
R3
R3
R3
R1
R1
R2
R4
A
R1
R2
R4
R4
R7
R5
R6
OH
R2
B
R5
R6
O
2.5 mol% PBu3
R5
R6
O
EtOH (50 mM)
30 °C
R7
O
R7
O
O
3b–3l
2b–2l
1b–1l
Time
/min
Ratio of Yield of 1
Entry
Substrate
R1
R2
R3
R4
R5
R6
R7
Product
1:2
/%
1
2
3
4
5
6
7
8
9
3b
3c
3d
3e
3f
3g
3h
3i
Cl
OMe
H
OMe
OMe
H
H
H
H
H
H
H
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
Cl
Br
H
H
H
H
H
H
H
H
H
H
1b
1c
1d
1e
1f
1g
1h
1i
5
20
5
10
15
5
15
30
30
5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
62:38
91
99
95
93
88
93
98
59
58
93
99
3j
3k
3l
1j
1k
1l
59:41
>95:5
>95:5
10
11
H
H
H
H
H
H
OMe
H
H
H
OMe
5
142 | Chem. Lett. 2015, 44, 141–143 | doi:10.1246/cl.140910
© 2015 The Chemical Society of Japan

R
R
R'
R'
O
PBu3
O
O
Ph
H O
H
O
O
PBu3
A
Aurone 1
Flavone 2
R
R'
OH
O
B
PBu3
Ph
A
R'
H
O
PBu3
H
O
R'
O
Ar
H O
R
PBu3
H
O
o-Alkynoylphenol 3
H
O
9
B
H
EtO–
8
–OEt
EtO–
R'
EtO–
PBu3
Ar
H
O
H
O
R'
6-endo
cyclization
PBu3
5-exo
cyclization
R
H
HO
O
H OEt
Enone 5
Allenol 4
Figure 3. A reaction mechanism for PBu3-catalyzed 5-exo cyclization of o-alkynoylphenol 3 leading to aurone 1.
6 (93%, D). Thus, the PBu3-catalyzed reaction of 3a is
performed via the formation of the carbanion adjacent to the
B-ring, as in 7, which is generated by the 5-exo cyclization in 4.
A plausible reaction mechanism of the PBu3-catalyzed
5-exo cyclization of o-alkynoylphenol 3 is depicted in Figure 3.
The 1,4-addition of PBu3 to 3 initially occurs similar to the
Morita-Baylis-Hillman reaction11 and protonation of the result-
ing allenolate in EtOH would be immediately performed leading
to allenol 4 in EtOH. Due to the strongly inductive effect of an
electron-withdrawing phosphonium moiety, the 5-exo cycliza-
tion of phenol, followed by subsequent protonation by EtOH
would smoothly proceed, prior to isomerization to the enone 5,
to afford the intermediate 8. Deprotonation by ethoxide induces
the elimination of PBu3 via the transition state A rather than B,
due to steric hindrance between the phenyl ring and the enol
moiety, to selectively afford the 5-exo cyclized (Z)-aurone 1. On
the other hand, allenol 4 could also be converted to enone 5
when the 5-exo cyclization of allenol 4 is slower, such as in the
reaction of 3i and 3j possessing an electron-withdrawing
halogen atom on the A-ring. As such, the 6-endo cyclization
of the resulting 5 would proceed through 9 to provide flavone 2.
In summary, we demonstrated the organocatalytic regiose-
lective cyclization of o-alkynoylphenol leading to aurone
derivatives. A catalytic amount of PBu3 smoothly induced the
regioselective cyclization of o-alkynoylphenols 3 at ambient
temperature. 5-exo cyclized aurones 1 were afforded in high to
excellent yields without the formation of the corresponding
flavones 2, except for substrates possessing an electron-with-
drawing halogen atom on the A-ring. It should be noted that the
use of protic media, such as EtOH, could be crucial for high
yields and regioselectivity. Furthermore, the reaction conditions
we developed should be useful for the synthesis of a variety of
aurone derivatives, including biologically active natural products.
Supporting Information is available electronically on J-STAGE.
References and Notes
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This study was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas (No. 2105), and partially sup-
ported by the Platform for Drug Discovery, Informatics, and
Structural Life Science from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Chem. Lett. 2015, 44, 141–143 | doi:10.1246/cl.140910
© 2015 The Chemical Society of Japan | 143