DBU-Catalyzed Michael Reaction of Enones with 1,3-Diketones and the Subsequent Iodine-Mediated Transformation of the Adducts to Polysubstituted Phenols

Article abstract of DOI:10.1055/s-0037-1611577

An efficient DBU-catalyzed Michael reaction of enones with 1,3-diketones has been developed for the gram-scale preparation of the Michael adducts. It is attractive that most of the adducts can be obtained with high purity through simple filtration. A conv

Full text of DOI:10.1055/s-0037-1611577

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–N
paper
A
en
C.-B. Miao et al.
Paper
Synthesis
DBU-Catalyzed Michael Reaction of Enones with 1,3-Diketones
and the Subsequent Iodine-Mediated Transformation of the
Adducts to Polysubstituted Phenols
OH
R3
R2
Chun-Bao Miao*
Mei-Ling Chen
Xiao-Qiang Sun
0
0
0
0-0
0
0
3-
4
6
6
6-2
6
1
9
O
Ar
R2
Ar
R1
R1
Hai-Tao Yang
0
0
0
0-0
0
0
1-9
8
0
3-5
4
5
2
O
O
OH
(R3 = H)
O
R3
R3
Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology, Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center, School of Petrochemical
Engineering, Changzhou University, No. 1, Gehu Road,
Wujin District, Changzhou 213164, P. R. of China
estally@yahoo.com
(1) DBU (cat.)
(2) I2, DBU
R
R
R
R
24 examples
up to 85% yield
for the phenol product
OH
O
(R3 = H)
R1
R2
R1
R2
Received: 12.02.2019
Accepted after revision: 24.03.2019
Published online: 18.04.2019
phenols.8a–d However, these approaches always suffer from
pre-installation of directing groups, high reaction tempera-
ture, long reaction time, and most of the products were re-
stricted to 3,5-diarylphenols. As for the direct construction
of phenols from 1,3-diketones/-ketoesters and enones un-
der basic conditions, a tethered auxiliary group such as ni-
tro or isocyanide was required.8e,f The reaction of 1,3-dia-
rylpropan-2-ones with chalcones or cinnamaldehydes gave
access to sterically hindered polyarylphenols;8g however,
the two aryl groups were necessary for the success of reac-
tion. Recently, oxidative metal-catalyzed aromatization of
cyclohex-2-enones or cyclohexones into phenols has made
extensive progress.9 Not long ago, a metal-free iodine-cata-
lyzed approach to phenols using DMSO as the oxidant was
reported.10 However, these cyclohex-2-enones should be
prepared from enones beforehand through 2–3 steps of re-
action and a long reaction time was always required. In our
previous work, we have reported the base-controlled con-
version of Michael adducts of enones with malonates into
cyclopropane, -hydroxymalonate, and oxetane derivatives
with high selectivity in the presence of I2.11a Later, we real-
ized the I2-mediated synthesis of azetidines, 2,4-dioxo-1,3-
diazabicyclo[3.2.0] compounds, and polysubstituted dihy-
drofurans/furans using a similar approach.11b,c Li and Gao
reported the I2-mediated construction of dihydropyrroles
from enones and -enamine carbonyl compounds.11d As
part of our on-going study in the iodine-promoted reac-
tion,12 we report here an efficient I2-mediated conversion of
the Michael adducts of enones with 1,3-diketones into vari-
ous polysubstituted phenols.
DOI: 10.1055/s-0037-1611577; Art ID: ss-2019-f0089-op
Abstract An efficient DBU-catalyzed Michael reaction of enones with
1,3-diketones has been developed for the gram-scale preparation of the
Michael adducts. It is attractive that most of the adducts can be ob-
tained with high purity through simple filtration. A convenient I2-medi-
ated transformation of the adducts to polysubstituted phenols has also
been exploited. This conversion is remarkable with the cyclization and
aromatization processes by using DBU as the base and I2 as the oxidant.
Furthermore, hydroxylated (E)-stilbene derivatives can be easily pre-
pared by using this method. The readily available starting materials,
metal-free and mild conditions make this approach simple and practi-
cal.
Key words polysubstituted phenol, 1,3-diketone, enone, iodine, DBU
Polysubstituted phenols are a class of important organic
compounds and key skeletons found in a variety of bioac-
tive compounds, natural products, agricultural and fine
chemicals, and functional polymers.1 Therefore, it is of con-
tinuous interest to develop an efficient and simple ap-
proach to access polysubstituted phenols. The strategies for
their synthesis can be classified as two main types based on
the starting materials: (1) Using aromatic precursors in-
cluding direct conversion of the hydrogen, halo, or amino
group on the aromatic ring into hydroxyl group2 and metal-
catalyzed cross-coupling reaction of phenols or halogenat-
ed phenols.3 (2) Using nonaromatic precursors including
benzannulation of vinylketenes,4 furan-tethered or -ke-
toester-tethered alkynes,5 cyclopropenes or cycloprope-
nones,6 cyclobutenones,7 and cyclocondensations of enones
with substituted acetones.8 Among these versatile starting
materials, enones are readily available as bulk chemicals.
The reaction of N-acetonylpyridinium bromide, 1-(ben-
zotriazol-1-yl)propan-2-one, or 2-fluoro--ketoesters with
enones led to the formation of 3,5- or 3,4,5-substituted
During the preparation of raw material 2a, we found a
good method for its large-scale preparation with no re-
quirement of column chromatographic separation. Using
DBU as the base catalyst, the reaction of 5 mmol of chal-
cone 1a with 1.5 equivalents of acetylacetone in DMSO was
completed within 1.5 hours [for more details of the screen-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

B
C.-B. Miao et al.
Paper
Synthesis
ing of conditions, see the Supporting Information (SI)]. Af-
ter quenching with dilute hydrochloric acid, addition of
ethanol and water, and then filtration gave the product 2a
in 85% yield with very high purity (Scheme 1).
Table 1 Screening of the Reaction Conditions
O
OH
OH
O
I
O
base
+
+
I2
solvent (3 mL), rt
Ph
Ph
Ph
O
Ph
Ph
O
Ph
O
O
2a
3a
3a'
(0.5 mmol)
O
O
O
DBU (0.15 equiv)
O
O
O
+
Ph
Ph
O
O
DMSO (10 mL), rt, 1.5 h
85%
OH
Ph
Ph
O
O
1a (10 mmol)
(1.5 equiv)
2a
Ph
Ph
Ph
Ph
Ph
Ph
O
Scheme 1 Large-scale preparation of Michael adduct of aceteylace-
tone with chalcone 1a
I
II
O
III
not observed
Entry
Base
2a/I2/base
Solvent
Time Yield of Yieldof
(h) 3a (%) 3a′ (%)
Our study was initiated with the reaction of Michael ad-
duct 2a with I2 using Na2CO3, NaOAc, or DBU as the base ac-
cording to our previously used conditions (Table 1).11 No
desired cyclopropane I, oxetane II, or -hydroxylacetylace-
tone III was generated (Table 1, entries 1–3). To our sur-
prise, when DBU was used as the base the unexpected 3,5-
diphenylphenol (3a) and 2-iodo-3,5-diphenylphenol (3a′)
was obtained in 26% and 16% yield, respectively (entry 3).
However, considerable amount of 2a remained unreacted.
Although increasing the amount of DBU to 4 equivalents
improved the yield of 3a to 38%, the selectivity was still un-
satisfactory (3a:3a′ = 1.41:1, entry 4). Later, various sol-
vents such as DMF, EtOH, CH2Cl2, THF, CH3CN, DMSO, and
EtOAc were screened with DBU as the base (entries 5–10).
The results showed that CH3CN was the best solvent, afford-
ing 3a in 82% yield with the best selectivity as 3a:3a′ up to
9:1. It was attractive that the reaction proceeded rapidly
and was completed within 30 minutes (entry 7). The prod-
uct 3a′ was proven to be generated from the further iodina-
tion of 3a with iodine under basic conditions. The slow dis-
solution of iodine in CH3CN decreased its concentration in
the reaction mixture, which was probably the main reason
for the formation of less by-product 3a′. Other bases such as
DMAP, Et3N, piperidine, morpholine, and pyrrolidine were
also evaluated with CH3CN as the solvent (entries 11–15).
No reaction occurred when using DMAP or Et3N as the base.
With piperidine or morpholine as the base, the reaction
proceeded very slowly. Even prolonging the reaction time
to 18 hours, considerable amount of 2a remained unreact-
ed. When pyrrolidine was used as the base, although the re-
action proceeded quickly, partial retro-Michael reaction of
2a to chalcone occurred and the yield as well as selectivity
was unsatisfactory. Finally, the optimal reaction conditions
were established by employing DBU as the base and CH3CN
as the solvent for the conversion of 2a into 3a (entry 7).
Broad substrate compatibility for the two-step synthesis
of 3,5-disubstituted phenols from enones and acetylace-
tone is shown in Table 2. Most of the Michael addition reac-
tion proceeded well to give the adducts 2 in good yields
with no requirement of column chromatography separa-
tion. Only the products 2k–m and 2o needed to be isolated
by column chromatography. When R1 is an electron-rich
1
2
Na2CO3
NaOAc
DBU
1:1.1:2.2
1:0.2:0.2
1:1.1:2.2
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
1:1.1:4
DMF
7
0
0
0
0
THF
7
3
EtOH
0.5
0.5
1
26
38
46
40
82
42
51
28
trace
0
16
27
20
27
9
4
DBU
EtOH
5
DBU
CH2Cl2
THF
6
DBU
1
7
DBU
CH3CN
DMSO
DMF
0.5
1
8
DBU
26
23
31
0
9
DBU
1
10
11
12
13
14
15
DBU
EtOAc
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1
DMAP
Et3N
18
18
18
0
piperidine
pyrrolidine
morpholine
25
33
21
17
19
trace
0.5
18
aryl group, a longer reaction time was required. By chang-
ing R2 to a methyl group, only a trace amount of the Michael
addition product was obtained in the first step of the reac-
tion. As for the second step of I2-mediated cyclization to
phenol, most of the reactions proceeded quickly (0.5–1 h)
and the corresponding 3,5-disubstituted phenols were ob-
tained in good yields when R1 and R2 were both aryl groups
(Table 2, entries 1–12). No dramatic electronic effect of the
substituent on the phenyl ring was observed. A furyl and
thienyl group substituted phenol also could be prepared in
good yields (entries 11 and 12). When R1 was a methyl
group or an ester group, although the Michael addition re-
action furnished 2m or 2o in excellent yield, the second-
step of reaction gave a complex mixture (entries 13 and 15).
When R2 was a strong electron-deficient aryl group, no
Michael addition product was obtained (Scheme 2). Instead,
the cyclization products 4p (4q) and 5p (5q) were produced
through the further nucleophilic addition to carbonyl group
due to its enhancement of electrophilicity. The keto and
enol form products were hard to separate on a silica gel col-
umn due to the tautomerization (recrystallization twice
from ethanol provided the pure enol form product 5p and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

C
C.-B. Miao et al.
Paper
Synthesis
Table 2 Generality for the DBU-Catalyzed Michael Addition of Enones with Acetylacetone and the Subsequent I2-Mediated Transformation to Phenols
O
OH
O
I2 (1.1 equiv)
O
O
O
DBU (4 equiv)
CH3CN, rt
DBU (0.15 equiv)
O
R1
R2
+
DMSO, rt
R1
R2
R1
R2
(1.5 equiv)
Conditions A
1
Conditions B
3
2
Conditions A: 5 mmol of 1 and 4 mL of DMSO
Conditions B: 0.5 mmol of 2 and 3 mL of CH3CN
Entry
Substrate
R1
Ph
R2
Ph
Time (h)
Product
Yield of 2 (%) Time (h)
Product
Yield of 3 (%)
1
2
1a
1b
1c
1d
1e
1f
1.5
3
2a
2b
2c
85
80
65
40
76
86
87
80
81
71
82
74
90
trace
90
0.5
1
3a
3b
3c
3d
3e
3f
81
4-MeC6H4
4-MeOC6H4
4-NMe2C6H4
3,4-OCH2OC6H3
4-ClC6H4
4-NO2C6H4
Ph
Ph
77
3
Ph
6
0.5
0.5
1.5
0.5
4.5
1
73
4
Ph
12
18
1
2d
2e
2f
75
5
Ph
83
6
Ph
80
7
1g
1h
1i
Ph
3
2g
2h
2i
3g
3c
3b
3f
76
8
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
5
75
9
Ph
1.5
1
2
73
10
11
12
13
14
15
1j
Ph
2j
0.5
0.5
0.5
5
70
1k
1l
2-furyl
2
2ka
2la
2ma
2n
2oa
3k
3l
69
2-thienyl
Me
2
80
1m
1n
1o
0.5
10
0.5
3m
3m
3o
complex
63
Ph
Me
0.5
5
CO2Me
Ph
complex
a Isolated by column chromatography.
the keto form product 4q, respectively). Next, treating the
mixture of 4p and 5p with I2/DBU, the corresponding phe-
nol 3g was obtained in 57% yield. Likewise, a 2-pyridyl
group substituted phenol 3q was generated in 88% yield.
In order to extend our methods to the synthesis of 3,4,5-
trisubstituted phenols, an electron-withdrawing ester
group and a methyl group was introduced at 2-position of
enone, respectively (1r and 1s, Scheme 2). The Michael re-
action of acetylacetone with 1r gave the similar result as
that of 1p and 1q, giving the cyclization products 4r and 5r
(recrystallization from ethanol provided the keto form
product 4r). However, the reaction of acetylacetone with 1s
catalyzed by DBU only gave a trace amount of product. We
found that the Cu(ClO4)2 could catalyze the addition reac-
tion and furnished 39% yield of the Michael adduct 2s ac-
companied by the further condensation product 2s′ in 28%
yield. The subsequent I2-mediated transformation of 4r/5r
and 2s afforded the corresponding phenols 3r and 3s in 93%
and 55% yield, respectively. However, the reaction of 2s′
with I2 in the presence of DBU did not provide the phenol
3s.
and cardioprotection. (E)-Resveratrol and (Z)-combretasta-
tin A-4 are the two representative compounds.13 (E)-Res-
veratrol has been suggested as an anticancer agent via the
inhibition of cell proliferation and (Z)-combretastatin A-4
also displayed prominent antitumor activity. Therefore, the
synthesis of new hydroxylated stilbene derivatives and
their bioactivity evaluation have received much attention
and interests in medicinal chemistry.14 To our knowledge,
most of the strategies relied on the construction of the C(vi-
nyl)–Ar bond through Pd-catalyzed cross couplings or the
creation of the C=C bonds by means of Wittig type reaction.
The 1,5-diarylpenta-1,4-dien-3-ones 6, which could be
easily prepared from the condensation of acetone with sub-
stituted benzaldehydes, was subjected to the reaction with
acetylacetone and gave a mixture of Michael adducts 7 and
the cyclization products 8/9 in good yields. Electron-donat-
ing group on the phenyl ring resulted in the need of a much
longer reaction time. Treating the mixture of 7, 8, and 9
with I2/DBU afforded the desired hydroxylated stilbene de-
rivatives 10a–d in good yields (Table 3).
From the structural perspective of compounds 10, both
aryl groups are the same. To introduce different aryl groups
in phenols 10, the unsymmetrical 1,5-diarylpenta-1,4-
dien-3-one 6 with a methoxy- and nitro group on the 4-po-
sition of each phenyl ring was subjected to the reaction.
However, the Michael addition step gave a very complex
Inspired by these good results, we next turned our at-
tention to the synthesis of 3-hydroxylated (E)-stilbenes
through the developed method. Hydroxylated stilbenes are
widespread in nature and have been reported to show a
range of biological activities such as antioxidant, antitumor,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

D
C.-B. Miao et al.
Paper
Synthesis
O
O
OH
O
OH
O
I2 (1.1 equiv)
OH
OH
O
O
DBU (4 equiv)
DBU (0.15 equiv)
+
CH3CN, rt., 0.5 h
57%
DMSO, rt., 0.5 h
72%
NO2
NO2
NO2
(0.15 equiv)
4p
5p
1p
1q
1r
NO2
3g
OH
O
O
OH
O
O
I2 (1.1 equiv)
OH
OH
N
O
O
DBU (4 equiv)
DBU (0.15 equiv)
+
DMSO, 40 °C, 1.5 h
86%
CH3CN, rt., 0.5 h
88%
N
N
N
4q
5q
(0.15 equiv)
3q
OH
OH
O
O
O
I2 (1.1 equiv)
O
DBU (4 equiv)
O
O
DBU (0.15 equiv)
OH
Ph
OH
Ph
Ph
Ph
+
CH3CN, rt., 0.5 h
93%
Ph
DMSO, rt., 2.5 h
50%
Ph
CO2Et
O
OEt
CO2Et
CO2Et
4r
3r
(0.15 equiv)
5r
O
OH
O
O
I2 (1.1 equiv)
DBU (4 equiv)
O
CH3
CH3CN, rt., 2.5 h
55%
O
O
2s (39%)
3s
Cu(ClO4)2•6H2O (0.4 equiv)
THF, 80 °C, 24 h
+
+
OH
O
(0.15 equiv)
I2 (1.1 equiv)
1s
DBU (4 equiv)
×
CH3CN, rt., 2.5 h
2s' (28%)
Scheme 2 Substrate scope expansion
mixture and the I2-mediated transformation gave a mixture
of two kinds of phenols with poor selectivity. To achieve the
goal, 1,5-diarylpenta-2,4-dien-1-ones 11 containing differ-
ent aryl substituents, which could be easily obtained
through the condensation reaction of aryl methyl ketones
with cinnamaldehyde derivatives, were used in the reac-
tion. The Michael addition step was similar to that of 6 and
gave a mixture of Michael adducts 12 and the cyclization
products 13/14 in moderate to good yields, albeit a much
longer reaction time was needed. Treating the mixture of
12, 13, and 14 with I2/DBU also could deliver the corre-
sponding hydroxylated stilbene derivatives 15 with differ-
Table 3 Synthesis of Hydroxylated Stilbene Derivatives from 1,5-Diarylpenta-1,4-dien-3-ones
O
O
O
O
OH
I2 (1.1 equiv)
R
R
6
7
R
R
DBU (4 equiv)
DBU (0.15 equiv)
+
OH
O
O
O
CH3CN, rt
O
O
DMSO, rt
+
Conditions B
10
R
R
Conditions A
OH
OH
(1.5 equiv)
R
R
R
R
9
8
Conditions A: 5 mmol of 6 and 4 mL of DMSO
Conditions B: 0.5 mmol of the mixture 7 / 8 / 9 and 3 mL of CH3CN
Entry
Substrate
R
Time (h)
Product
Yield of 7 + 8 + 9 (%) Time (h)
Product
Yield of 10 (%)
1
2
3
4
6a
6b
6c
6d
H
1.5
15
8
7a, 8a, 9a
7b, 8b, 9b
7c, 8c, 9c
7d, 8d, 9d
88
90
77
87
1
10a
10b
10c
10d
71
79
75
73
OMe
Me
Cl
0.5
1
2
0.5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

E
C.-B. Miao et al.
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Synthesis
Table 4 Synthesis of Hydroxylated Stilbene Derivatives from 1,5-Diarylpenta-2,4-dien-1-ones
O
O
O
O
OH
I2 (1.1 equiv)
R1
R2
R1
R2
11
12
DBU (4 equiv)
DBU (0.15 equiv)
+
CH3CN, rt
OH
O
+
O
O
R1
R2
O
O
DMSO, rt
15
Conditions B
Conditions A
OH
OH
(1.5 equiv)
R1
R2
R1
Conditions A: 5 mmol of 11 and 4 mL of DMSO
R2
14
13
Conditions B: 0.5 mmol the mixture 12 / 13 / 14 and 3 mL of CH3CN
Entry
Substrate
R1
R2
Time (h)
Products
Yield of 12 + 13 + 14 Time (h)
(%)
Product
Yield of 15 (%)
1
2
3
4
5
6
7
11a
11b
11c
11d
11e
11f
H
H
14
24
24
7
12a, 13a, 14a
12b, 13b, 14b
12c, 13c, 14c
12d, 13d, 14d
12e, 13e, 14e
12f, 13f, 14f
71
79
67
83
77
75
70
1.5
6
10a
15b
15c
15d
15e
15f
50
25
32
55
63
53
41
H
Me
MeO
Cl
H
9
H
1.5
1
H
NO2
H
8
Br
MeO
13
21
1
11g
H
12g, 13g, 14g
0.5
15g
ent substituents on the two phenyl rings (Table 4). Al-
though the yields were not satisfactory, the advantage of
this method depended on the variability of the two aryl
groups. When R2 is an electron-donating group such as
methyl or methoxy, the second step of reaction needed a
much longer time and the yield was very low (Table 4, en-
tries 2 and 3).
The feasibility of synthesizing diverse phenols using dif-
ferent substituted acetones was also investigated (Scheme
3). Excitingly, the addition of 3,5-heptanedione (16) with
chalcone 1a gave the cyclization product 17, which could be
converted into the 2,3,5-trisubstituted phenol 18 in 85%
yield under I2/DBU conditions. When one of the acetyl
groups in acetylacetone was replaced by benzoyl or 4-me-
O
O
OH
O
I2 (1.1 equiv)
OH
O
O
DBU (4 equiv)
DBU (0.15 equiv)
+
DMSO, rt., 5 h
50%
CH3CN, rt., 0.5 h
85%
1a
16 (1.5 equiv)
17
18
O
O
O
O
O
O
I2 (1.1 equiv)
DBU (0.15 equiv)
DMSO, rt., 4 h
58%
DBU (4 equiv)
complex mixture
+
CH3CN, rt, 4 h
1a
19 (1.5 equiv)
20
O
O
O
I2 (1.1 equiv)
O
O
O
DBU (4 equiv)
DBU (0.15 equiv)
complex mixture
+
CH3CN, rt, 4 h
DMSO, rt., 4 h
60%
1a
21 (1.5 equiv)
22
O
O
OH
O
O
EtO2C
COCH3
O
O
O
I2 (1.1 equiv)
EtO
DBU (0.15 equiv)
DMSO, 5 °C, 50 min
DBU (4 equiv)
+
OEt
23 (1.5 equiv)
+
CH3CN, rt, 12 h
1a
24, 85%
25, 28%
3a, 24%
Scheme 3 Attempts to prepare phenols from different substituted acetones
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

F
C.-B. Miao et al.
Paper
Synthesis
thoxyphenyl group, the Michael reaction occurred normally
to give the products 20 and 22, respectively. But in the sec-
ond step of reaction, both of them gave a complex mixture,
simultaneously with low conversion of 20/22. When ethyl
acetoacetate (23) was used instead of acetylacetone, the Mi-
chael addition proceeded well to give 24 in 85% yield in 50
minutes. The reaction of 24 with I2/DBU gave the main
cyclopropane product 25 within 40 minutes. By extending
the reaction time to 12 hours, 25 and 3a could be generated
in 28% and 24% yield, respectively. But, the treatment of 25
with DBU did not produce phenol 3a, which proves that 3a
is not formed from 25.
To make the experimental operation easier, the synthe-
sis of 3,5-diphenylphenol (3a) from chalcone and acetylace-
tone without isolation of the Michael adduct was tried.
Upon completion of the Michael addition, the product was
extracted with ethyl acetate. After drying and concentra-
tion, the crude product was treated with I2/DBU in CH3CN.
However, only a moderate yield of 3a (51%) was obtained.
The reason was that the surplus acetylacetone could react
with iodine, resulting in the consumption of iodine and
base. In order to illustrate the practicability of this method,
a gram-scale reaction was carried out with 10 mmol of 1a
and 15 mmol of acetylacetone, giving 3a in 71% yield
(Scheme 4).
to that of 36. There results ruled out the possibility of in-
volving 27 or 31 as an intermediate and also illustrated the
deacetylation must occur after the formation of C=C bonds.
Besides, the reaction of 20 or 22 with I2/DBU did not pro-
duce the corresponding phenol indicates that the acetyl is
essential to the reaction and has some interaction with the
hydroxyl group. Based on these results, we propose another
possible reaction pathway c. Iodination at the -position of
two carbonyl groups gives 32. Interconversion of chair con-
formation into boat conformation 33 and the subsequent
intramolecular nucleophilic substitution generates inter-
mediate 34. Elimination of acetic acid and hydrogen iodide
under basic conditions affords the phenol 3.
O
O
O
O
I2
R1
R2
DBU
R1
R2
2
DBU
31
O
O
O
O
O
O
O
I
I
I2
H2O
DBU
OH
R2
DBU
DBU
R1
R2
– H2O
path a
R1
R2
R1
R2
R1
26
keto form
29
28
27
OH
R3
O
OH
O
O
R2
R1
R2
R1
R2
R1
32
OH
R1
O
I
R3
30
3
OH
DBU
(1) DBU (0.15 equiv)
O
OH
R2
– HI, – HOAc
O
O
DMSO, rt., 1.5 h
Ph
Ph
O
+
O
enol form
HO
(2) I2 (1.1 equiv), DBU (4 equiv)
CH3CN, rt., 40 min
Ph
Ph
10 mmol
1.5 equiv
I
O
I
R2
3a (1.754 g, 71%)
O
R1
R2
O
Scheme 4 Gram-scale synthesis of 3a
34
R1
33
Scheme 5 Proposed reaction mechanism
A tentative reaction mechanism is proposed in Scheme
5. Intramolecular nucleophilic addition to carbonyl group
leads to the formation of 26 or its enol form. It was sure that
the iodine played an important role here because in the ab-
sence of iodine the cyclization proceeded extremely slowly.
The underlying cause is unclear at present. Three possible
reaction pathways might exist in the next reaction. In path
a, dehydration under basic conditions affords 27, which un-
dergoes iodination to give 28. The follow-up deacetylation
and dehydroiodination under basic conditions gives 30,
which is equal to the phenol 3. In path b, dehydration and
deacetylation of 26 delivers cyclohexenone 31, which un-
dergoes iodination and dehydroiodination to furnish the
phenol 3. In order to verify the two possible reaction path-
way, cyclohexenones 35 and 36 were prepared and subject-
ed to the reaction conditions, respectively (Scheme 6, see
SI). Although oxidative dehydrogenation of cyclohexenones
to access corresponding phenols had been well reported,
the reaction of 35 with I2/DBU only gave 3a and 3a′ in 12%
and 17% yield, respectively, and most of 35 was recovered
simultaneously. In the case of 36, almost no 3a was formed
as determined by TLC.15 The fact that reaction of 2s′ with
I2/DBU did not produce the phenol product 3s was similar
O
I2 (1.1 equiv)
DBU (4 equiv)
3a (12%) + 3a' (17%) + other unidentified products
CH3CN, rt, 5 h
Ph
Ph
35
O
O
O
OH
O
I2 (1.1 equiv)
DBU (4 equiv)
NaOH (0.2 equiv)
complex mixture
+
CH3CN, rt, 10 h
EtOH/H2O (4:1)
80 °C, 24 h
Ph
Ph
Ph
Ph
1a
36
Scheme 6 Control experiments
In conclusion, we have developed an efficient DBU-cata-
lyzed addition reaction of 1,3-diketones with enones. Most
of the products were isolated in high purity via simple fil-
tration; this is attractive for their large-scale preparation. A
novel methodology for the transformation of the Michael
adducts to polysubstituted phenols under I2/DBU condi-
tions is exploited. Furthermore, through elaborate selection
of the enone substrates, hydroxylated stilbene derivatives
also can be easily prepared. The cheap reagents, no require-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

G
C.-B. Miao et al.
Paper
Synthesis
ment of heating, and mild metal-free conditions make this
protocol very simple, practical, and easy to handle.
1H NMR (300 MHz, CDCl3):  = 7.84 (d, J = 7.1 Hz, 2 H), 7.52 (tt, J = 7.3,
1.3 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.06 (d, J = 8.8 Hz, 2 H), 6.59 (d, J =
8.8 Hz, 2 H), 4.28 (d, J = 11.1 Hz, 1 H), 4.12 (ddd, J = 11.1, 8.9, 4.3 Hz, 1
H), 3.26 (dd, J = 16.1, 8.9 Hz, 1 H), 3.14 (dd, J = 16.0, 4.3 Hz, 1 H), 2.90
(s, 6 H), 2.27 (s, 3 H), 1.89 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 204.0, 203.7, 198.3, 149.7, 137.0, 133.1,
128.9, 128.6, 128.3, 127.6, 112.8, 74.9, 43.6, 40.65, 40.56, 30.1, 30.0.
1H and 13C NMR (broadband decoupled) were recorded on 300 and
500 MHz (75 and 125 MHz for 13C NMR) spectrometers. Melting
points were determined on a micromelting point apparatus and are
uncorrected. Flash column chromatography was performed on silica
gel (200–300 mesh). HRMS were obtained on an Thermo Scientific
LTQ Orbitrap XL equipped with an ESI source (positive mode).
HRMS (ESI): m/z [M + H]+ calcd for C22H26NO3: 352.1913; found:
352.1910.
2e
Michael Addition Products 2a–j and Phenols 3a–g; General Proce-
dure
White solid; yield: 1.338 g (76%); mp 141–142 °C.
1H NMR (300 MHz, CDCl3):  = 7.84 (d, J = 7.1 Hz, 2 H), 7.54 (tt, J = 7.3,
1.3 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 6.72 (t, J = 1.1 Hz, 1 H), 6.61–6.69
(m, 2 H), 5.90 (q, J = 1.4 Hz, 2 H), 4.26 (d, J = 11.0 Hz, 1 H), 4.15 (ddd,
J = 11.1, 8.9, 4.1 Hz, 1 H), 3.25 (dd, J = 16.3, 8.8 Hz, 1 H), 3.14 (dd, J =
16.2, 4.1 Hz, 1 H), 2.27 (s, 3 H), 1.94 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 203.5, 203.1, 197.8, 147.9, 146.7, 136.8,
134.0, 133.3, 128.7, 128.2, 121.5, 108.59, 108.55, 101.2, 74.7, 43.3,
41.0, 30.1, 30.0.
Step 1: A big tube (∅ 18 × 150 mm) was charged with enone 1 (5
mmol), acetylacetone (750 mg, 7.5 mmol), DBU (114 mg, 0.75 mmol),
and DMSO (5 mL). The mixture was stirred at rt until the completion
of reaction as determined by TLC (if the precipitated solid prevented
stirring, the mixture was kept standing). After quenching with dil HCl,
the mixture was dispersed in EtOH (10 mL) and H2O (15 mL). The sol-
id was filtered, washed with EtOH/H2O (1:1), and then dried to give
2a–j.
HRMS (ESI): m/z [M + H]+ calcd for C21H21O5: 353.1389; found:
Step 2: I2 (139.70 mg, 0.55 mmol) was added in one portion to a
stirred mixture of 2 (0.5 mmol) and DBU (304 mg, 2 mmol) in CH3CN
(3 mL). The reaction mixture was stirred at rt until the completion of
the reaction as determined by TLC. The mixture was diluted with
EtOAc (30 mL), then quenched with aq Na2S2O3 (15 mL, 10 mg/mL)
and 1 N dil HCl (15 mL). The aqueous phase was further extracted
with EtOAc (2 × 20 mL). The combined organic layers were washed
with sat. aq NaHCO3. The organic phase was dried (anhyd Na2SO4) and
concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel eluting with EtOAc/PE to provide the corre-
sponding products.
353.1382.
2f16
White solid; yield: 1.471 g (86%).
1H NMR (300 MHz, CDCl3):  = 7.82 (d, J = 7.1 Hz, 2 H), 7.54 (tt, J = 7.4,
1.2 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.23 (d, J = 8.8 Hz, 2 H), 7.18 (d, J =
8.7 Hz, 2 H), 4.29 (d, J = 10.9 Hz, 1 H), 4.21 (ddd, J = 11.0, 8.9, 4.1 Hz, 1
H), 3.30 (dd, J = 16.6, 8.5 Hz, 1 H), 3.18 (dd, J = 16.6, 3.9 Hz, 1 H), 2.27
(s, 3 H), 1.92 (s, 3 H).
2g17
2a16
White solid; yield: 1.536 g (87%).
White solid; yield: 1.312 g (85%).
1H NMR (300 MHz, CDCl3):  = 8.12 (d, J = 8.9 Hz, 2 H), 7.82 (d, J = 7.1
Hz, 2 H), 7.55 (tt, J = 7.4, 1.3 Hz, 1 H), 7.46 (d, J = 8.8 Hz, 2 H), 7.43 (t,
J = 7.5 Hz, 1 H), 4.30–4.42 (m, 2 H), 3.32–3.44 (m, 1 H), 3.22–3.32 (m,
1 H), 2.29 (s, 3 H), 1.97 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 202.5, 202.1, 196.9, 148.5, 147.1, 136.4,
133.7, 129.4, 128.9, 128.1, 124.0, 73.8, 42.3, 40.5, 30.2, 29.9.
1H NMR (300 MHz, CDCl3):  = 7.82 (d, J = 7.1 Hz, 2 H), 7.52 (tt, J = 7.4,
1.3 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.20–7.26 (m, 4 H), 7.11–7.19 (m,
1 H), 4.33 (d, J = 11.0 Hz, 1 H), 4.22 (ddd, J = 11.1, 8.8, 4.1 Hz, 1 H), 3.33
(dd, J = 16.4, 8.7 Hz, 1 H), 3.19 (dd, J = 16.3, 4.1 Hz, 1 H), 2.28 (s, 3 H),
1.89 (s, 3 H).
2b16
2h
White solid; yield: 1.290 g (80%).
White solid; yield: 1.356 g (80%); mp 132–133 °C.
1H NMR (300 MHz, CDCl3):  = 7.83 (d, J = 7.1 Hz, 2 H), 7.52 (tt, J = 7.4,
1.2 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.10 (d, J = 8.2 Hz, 2 H), 7.04 (d, J =
8.0 Hz, 2 H), 4.30 (d, J = 11.1 Hz, 1 H), 4.18 (ddd, J = 11.1, 8.9, 4.1 Hz, 1
H), 3.29 (dd, J = 16.2, 8.9 Hz, 1 H), 3.17 (dd, J = 16.3, 4.1 Hz, 1 H), 2.28
(s, 3 H), 2.25 (s, 3 H), 1.89 (s, 3 H).
1H NMR (300 MHz, CDCl3):  = 7.80 (d, J = 9.0 Hz, 2 H), 7.12–7.26 (m, 5
H), 6.87 (d, J = 9.0 Hz, 2 H), 4.33 (d, J = 11.1 Hz, 1 H), 4.20 (ddd, J = 11.1,
8.8, 4.2 Hz, 1 H), 3.84 (s, 3 H), 3.26 (dd, J = 15.9, 8.8 Hz, 1 H), 3.13 (dd,
J = 16.0, 4.2 Hz, 1 H), 2.29 (s, 3 H), 1.88 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 203.6, 203.3, 196.4, 163.6, 140.5, 130.5,
129.9, 128.9, 128.2, 127.4, 113.8, 74.6, 55.6, 42.8, 41.5, 30.1, 30.0.
HRMS (ESI): m/z [M + H]+ calcd for C21H23O4: 339.1596; found:
339.1590.
2c16
White solid; yield: 1.106 g (65%).
1H NMR (300 MHz, CDCl3):  = 7.82 (d, J = 7.2 Hz, 2 H), 7.52 (tt, J = 7.4,
1.2 Hz, 1 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.77 (d, J =
8.7 Hz, 2 H), 4.28 (d, J = 11.1 Hz, 1 H), 4.17 (ddd, J = 11.1, 8.9, 4.2 Hz, 1
H), 3.73 (s, 3 H), 3.27 (dd, J = 16.2, 8.8 Hz, 1 H), 3.16 (dd, J = 16.2, 4.2
Hz, 1 H), 2.28 (s, 3 H), 1.89 (s, 3 H).
2i
White solid; yield: 1.304 g (81%); mp 156–157 °C.
1H NMR (300 MHz, CDCl3):  = 7.72 (d, J = 8.2 Hz, 2 H), 7.12–7.26 (m, 7
H), 4.32 (d, J = 11.0 Hz, 1 H), 4.21 (ddd, J = 11.1, 8.8, 4.1 Hz, 1 H), 3.29
(dd, J = 16.2, 8.7 Hz, 1 H), 3.15 (dd, J = 16.2, 4.1 Hz, 1 H), 2.38 (s, 3 H),
2.28 (s, 3 H), 1.88 (s, 3 H).
2d
White solid; yield: 0.708 g (40%); mp 220–221 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

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C.-B. Miao et al.
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Synthesis
13C NMR (75 MHz, CDCl3):  = 203.5, 203.2, 197.5, 144.1, 140.5, 134.4,
129.3, 128.9, 128.3, 128.2, 127.3, 74.5, 43.0, 41.3, 30.0, 21.7.
HRMS (ESI): m/z [M + H]+ calcd for C21H23O3: 323.1647; found:
323.1639.
1H NMR (300 MHz, CDCl3):  = 7.59 (d, J = 7.1 Hz, 2 H), 7.43 (t, J = 7.3
Hz, 2 H), 7.35 (tt, J = 7.2, 1.2 Hz, 1 H), 7.30 (t, J = 1.4 Hz, 1 H), 7.05–7.12
(m, 2 H), 7.00 (dd, J = 2.2, 1.5 Hz, 1 H), 6.96 (dd, J = 2.2, 1.6 Hz, 1 H),
6.87 (d, J = 8.6 Hz, 1 H), 5.99 (s, 2 H), 5.39 (br s, 1 H).
13C NMR (75 MHz, CDCl3):  = 156.3, 148.2, 147.4, 143.5, 143.1, 140.9,
135.2, 128.9, 127.7, 127.3, 120.8, 118.7, 113.0, 112.9, 108.7, 107.8,
101.3.
2j16
White solid; yield: 1.214 g (71%).
1H NMR (300 MHz, CDCl3):  = 7.76 (d, J = 8.7 Hz, 2 H), 7.38 (d, J = 8.7
Hz, 2 H), 7.10–7.30 (m, 5 H), 4.31 (d, J = 10.9 Hz, 1 H), 4.18 (ddd, J =
11.0, 8.6, 4.5 Hz, 1 H), 3.26 (dd, J = 16.1, 8.5 Hz, 1 H), 3.18 (dd, J = 16.1,
4.6 Hz, 1 H), 2.28 (s, 3 H), 1.89 (s, 3 H).
3f10c
White solid; from substrate 1f, yield: 112.4 mg (80%), from substrate
1j, yield: 98.0 mg (70%).
1H NMR (300 MHz, CDCl3):  = 7.59 (d, J = 6.9 Hz, 2 H), 7.52 (d, J = 8.7
Hz, 2 H), 7.45 (t, J = 7.2 Hz, 2 H), 7.34-7.41 (m, 3 H), 7.32 (t, J = 1.5 Hz,
1 H), 7.05 (dd, J = 2.4, 1.6 Hz, 1 H), 7.00 (dd, J = 2.3, 1.6 Hz, 1 H), 5.30
(br s, 1 H).
3a18
White solid; from substrate 1a, yield: 100.5 mg (82%); from substrate
24, yield: 29.7 mg (24%).
1H NMR (300 MHz, CDCl3):  = 7.61 (d, J = 7.2 Hz, 4 H), 7.45 (t, J = 7.3
Hz, 4 H), 7.39 (t, J = 1.5 Hz, 1 H), 7.36 (t, J = 7.3 Hz, 2 H), 7.04 (d, J = 1.5
Hz, 2 H), 5.11 (br s, 1 H).
3g8d
Yellow solid; from substrate 1g, yield: 110.4 mg (76%); from substrate
4p + 5p, yield: 82.7 mg (57%).
1H NMR (300 MHz, DMSO-d6):  = 9.94 (s, 1 H), 8.31 (d, J = 8.8 Hz, 2
H), 8.00 (d, J = 8.9 Hz, 2 H), 7.73 (d, J = 7.1 Hz, 2 H), 7.49 (t, J = 7.4 Hz, 2
H), 7.45 (t, J = 1.5 Hz, 1 H), 7.40 (tt, J = 7.3, 1.2 Hz, 1 H), 7.143 (s, 1 H),
7.138 (s, 1 H).
3a′
Obtained from the preparation of 3a as a by-product; yellow oil;
yield: 16.7 mg (9%).
1H NMR (300 MHz, CDCl3):  = 7.57–7.63 (m, 2 H), 7.32–7.50 (m, 8 H),
7.25 (d, J = 2.2 Hz, 1 H), 7.13 (d, J = 2.2 Hz, 1 H), 5.67 (s, 1 H).
13C NMR (75 MHz, CDCl3):  = 155.5, 148.0, 144.3, 142.8, 139.6, 129.3,
129.0, 128.2, 128.1, 128.0, 127.1, 121.3, 112.1, 90.3.
HRMS (ESI): m/z [M + H]+ calcd for C18H14IO: 373.0089; found:
373.0090.
Michael Addition Products 2k, 2l, 2m, and 2o and Phenols 3k, 3l,
and 3m; General Procedure
Step 1: A big tube (∅ 18 × 150 mm) was charged with enone 1 (5
mmol), acetylacetone (750 mg, 7.5 mmol), DBU (114 mg, 0.75 mmol),
and DMSO (4 mL). The mixture was stirred at rt until the completion
of reaction (TLC analysis). The mixture was diluted with EtOAc and
then washed successively with 1 N dil HCl, sat. aq NaHCO3, and brine.
The organic phase was dried (anhyd Na2SO4), evaporated, and the res-
idue was purified by column chromatography on silica gel eluting
with EtOAc/PE to provide the corresponding products of 2k, 2l, 2m,
and 2o.
3b10c
Pale yellow solid; from substrate 1b, yield: 100.1 mg (77%), from sub-
strate 1i, yield: 94.90 mg (73%).
1H NMR (300 MHz, CDCl3):  = 7.61 (d, J = 6.9 Hz, 2 H), 7.51 (d, J = 8.1
Hz, 2 H), 7.44 (t, J = 7.3 Hz, 2 H), 7.32–7.39 (m, 2 H), 7.24 (d, J = 7.8 Hz,
2 H), 7.00–7.05 (m, 2 H), 5.30 (br s, 1 H), 2.40 (s, 3 H).
Step 2: The process for the subsequent I2-mediated phenol formation
was the same as Step 2 in the general procedure for the preparation of
3a–g.
3c18
Yellow solid; from substrate 1c, yield: 100.7 mg (73%), from substrate
1h, yield: 103.5 mg (75%).
1H NMR (300 MHz, CDCl3):  = 7.60 (d, J = 6.9 Hz, 2 H), 7.54 (d, J = 8.9
Hz, 2 H), 7.44 (t, J = 7.3 Hz, 2 H), 7.30–7.39 (m, 2 H), 7.00 (s, 1 H), 6.99
(s, 1 H), 6.97 (d, J = 8.9 Hz, 2 H), 5.27 (br s, 1 H), 3.85 (s, 3 H).
2k
Pale yellow solid; yield: 1.365 g (82%); mp 114–115 °C.
1H NMR (300 MHz, CDCl3):  = 7.83 (d, J = 8.5 Hz, 2 H), 7.41 (d, J = 8.6
Hz, 2 H), 7.27 (d, J = 1.8 Hz, 1 H), 6.22 (dd, J = 3.2, 1.8 Hz, 1 H), 6.05 (d,
J = 3.2 Hz, 1 H), 4.21–4.37 (m, 2 H), 3.30 (dd, J = 16.7, 7.4 Hz, 1 H), 3.19
(dd, J = 16.7, 3.6 Hz, 1 H), 2.24 (s, 3 H), 2.03 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 203.1, 202.9, 196.6, 153.2, 141.9, 139.8,
135.0, 129.7, 129.0, 110.7, 107.6, 70.9, 40.1, 34.6, 30.5, 29.6.
3d
Yellow solid; yield: 108.4 mg (75%); mp 116–117 °C.
1H NMR (300 MHz, CDCl3):  = 7.61 (d, J = 7.0 Hz, 2 H), 7.51 (d, J = 8.9
Hz, 2 H), 7.43 (t, J = 7.3 Hz, 2 H), 7.31–7.38 (m, 2 H), 6.93–7.02 (m, 2
H), 6.81 (d, J = 8.9 Hz, 2 H), 5.44 (br s, 1 H), 2.99 (s, 6 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H17ClO4Na: 355.0713; found:
355.0710.
13C NMR (75 MHz, CDCl3):  = 156.5, 150.2, 143.3, 141.2, 129.4, 128.8,
127.9, 127.6, 127.3, 118.0, 113.4, 112.3, 112.2, 40.9.
2l
White solid; yield: 1.294 g (74%); mp 89–90 °C.
HRMS (ESI): m/z [M + H]+ calcd for C20H20NO: 290.1545; found:
290.1538.
1H NMR (300 MHz, CDCl3):  = 7.80 (d, J = 8.7 Hz, 2 H), 7.40 (d, J = 8.7
Hz, 2 H), 7.12 (dd, J = 4.5, 1.7 Hz, 1 H), 6.80–6.87 (m, 2 H), 4.53 (ddd,
J = 10.3, 8.4, 4.3 Hz, 1 H), 4.35 (d, J = 10.3 Hz, 1 H), 3.31 (dd, J = 16.5,
8.4 Hz, 1 H), 3.22 (dd, J = 16.5, 4.3 Hz, 1 H), 2.26 (s, 3 H), 2.02 (s, 3 H).
3e10c
Yellow oil; yield: 120.4 mg (83%).
13C NMR (75 MHz, CDCl3):  = 203.0, 202.8, 196.5, 143.5, 139.9, 135.1,
129.7, 129.1, 127.0, 126.2, 124.6, 74.4, 43.6, 36.5, 30.3, 30.1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

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C.-B. Miao et al.
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Synthesis
HRMS (ESI): m/z [M + K]+ calcd for C18H17ClO3SK: 387.0224; found:
387.0223.
2m19
completion of reaction (TLC analysis). The mixture was diluted with
EtOAc and then washed successively with 1 N HCl, sat. aq NaHCO3,
and brine. The organic phase was dried (anhyd Na2SO4) and evaporat-
ed. The residue was purified by column chromatography on silica gel
eluting with EtOAc/PE to provide the corresponding products of 4p
and 5p as a mixture (recrystallization twice from EtOH provided the
pure enol form product 5p).
White solid; yield: 1.107 g (90%).
1H NMR (300 MHz, CDCl3): d = 7.95 (d, J = 7.1 Hz, 2 H), 7.58 (tt, J = 7.3,
1.3 Hz, 1 H), 7.47 (t, J = 7.4 Hz, 2 H), 3.83 (d, J = 8.6 Hz, 1 H), 2.95–3.11
(m, 2 H), 2.84 (dd, J = 17.2, 9.3 Hz, 1 H), 2.24 (s, 3 H), 2.20 (s, 3 H), 1.00
(d, J = 6.8 Hz, 3 H).
Step 2: The process for the subsequent I2-mediated phenol formation
(a mixture of 4p and 5p was used) was the same as Step 2 in the gen-
eral procedure for the preparation of 3a–g.
2o
Colorless oil; yield: 1.305 g (90%).
4p/5p
1H NMR (300 MHz, CDCl3):  = 7.93 (d, J = 7.1 Hz, 2 H), 7.58 (tt, J = 7.4,
1.3 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 4.41 (d, J = 7.5 Hz, 1 H), 3.86 (ddd,
J = 7.4, 5.8, 5.1 Hz, 1 H), 3.65 (s, 3 H), 3.53 (dd, J = 18.4, 6.0 Hz, 1 H),
3.25 (dd, J = 18.4, 5.0 Hz, 1 H), 2.32 (s, 3 H), 2.26 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 203.1, 202.9, 197.6, 173.0, 136.1, 133.5,
128.6, 128.0, 67.4, 52.3, 39.4, 37.2, 30.4, 30.1.
Mixture of 4p:5p (1:4.7); white solid; yield: 1.271 g (72%).
1H NMR (300 MHz, CDCl3):  = 16.27 (s, 1 H), 8.18 (d, J = 9.0, Hz, 2 H),
7.64 (d, J = 9.0 Hz, 2 H), 7.30 (d, J = 7.5 Hz, 2 H), 7.16–7.26 (m, 3 H),
4.14 (dd, J = 10.5, 6.5 Hz, 1 H), 3.05 (dd, J = 18.3, 1.3 Hz, 1 H), 2.66 (dd,
J = 18.3, 3.3 Hz, 1 H), 2.40 (s, 1 H), 2.36 (ddd, J = 14.0, 6.5, 3.3 Hz, 1 H),
1.98 (dd, J = 14.1, 10.7 Hz, 1 H), 1.75 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H19O5: 291.1232; found:
HRMS (ESI): m/z [M + H]+ calcd for C20H20NO5: 354.1341; found:
291.1226.
354.1351.
3k
Reaction 1q/1r with Acetylacetone and the Subsequent I2-Mediat-
ed Phenol Formation
Pale yellow solid; yield: 93.1 mg (69%); mp 109–110 °C.
1H NMR (300 MHz, DMSO-d6):  = 9.81 (s, 1 H), 7.75–7.78 (m, 1 H),
7.70 (d, J = 8.7 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.42 (t, J = 1.4 Hz, 1 H),
7.12 (dd, J = 2.2, 1.4 Hz, 1 H), 7.02 (dd, J = 3.5, 0.6 Hz, 1 H), 6.95 (dd, J =
2.1, 1.5 Hz, 1 H), 6.61 (dd, J = 3.4, 1.8 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6):  = 158.3, 152.9, 143.0, 140.9, 138.8,
132.5, 132.2, 128.9, 128.5, 112.9, 112.8, 112.1, 109.6, 106.4.
Step 1: A big tube (∅ 18 × 150 mm) was charged with enone 1q or 1r
(5 mmol), acetylacetone (750 mg, 7.5 mmol), DBU (114 mg, 0.75
mmol), and DMSO (5 mL). The mixture was stirred (for 1q, at 40 °C;
for 1r, at rt) until the completion of reaction as determined by TLC
and then dispersed in EtOH (10 mL) and H2O (15 mL). The precipitate
was filtered to give a mixture of 4q (4r) and 5q (5r) as white solid (re-
crystallization from EtOH the pure keto form product 4q and 4r).
HRMS (ESI): m/z [M + H]+ calcd for C16H12ClO2: 271.0526; found:
271.0527.
Step 2: The process for the subsequent I2-mediated phenol formation
(a mixture of 4q/4r and 5q/5r was used) was the same as Step 2 in the
general procedure for the preparation of 3a–g.
3l
Brown solid; yield: 114.4 mg (80%); mp 101–102 °C.
4q/5q
1H NMR (300 MHz, DMSO-d6):  = 9.83 (s, 1 H), 7.70 (d, J = 8.6 Hz, 2
H), 7.53–7.60 (m, 2 H), 7.51 (d, J = 8.6 Hz, 2 H), 7.35 (t, J = 1.4 Hz, 1 H),
7.14 (dd, J = 5.1, 3.6 Hz, 1 H), 7.06 (t, J = 1.8 Hz, 1 H), 6.97 (t, J = 1.8 Hz,
1 H).
13C NMR (75 MHz, DMSO-d6):  = 158.4, 143.3, 141.2, 138.8, 135.7,
132.6, 128.9, 128.6, 128.5, 125.7, 124.1, 114.8, 113.0, 111.8.
Mixture of 4q:5q (1:2); white solid; yield: 1.389 g (86%).
1H NMR (500 MHz, CDCl3):  = 16.36 (s, 1 H, enol), 8.55 (d, J = 5.1 Hz, 1
H, ketone), 8.54 (d, J = 5.1 Hz, 1 H, enol), 7.76 (t, J = 7.7 Hz, 1 H, ke-
tone), 7.70 (t, J = 7.7 Hz, 2 H, enol), 7.46 (d, J = 7.9 Hz, 1 H, ketone),
7.31 (d, J = 8.0 Hz, 1 H, enol), 7.26–7.28 (m, 1 H, ketone), 7.24 (dd, J =
7.3, 4.8 Hz, 1 H, enol), 7.17 (d, J = 8.0 Hz, 2 H, ketone), 7.08–7.14 (m, 6
H, ketone + enol), 5.39 (s, 1 H, enol), 4.99 (s, 1 H, ketone), 4.19 (dd, J =
10.6, 6.2 Hz, 1 H, enol), 4.06 (td, J = 12.5, 3.8 Hz, 1 H, ketone), 3.85 (d,
J = 12.5 Hz, 1 H, ketone), 3.06 (d, J = 14.1 Hz, 1 H, ketone), 3.02 (d, J =
18.2 Hz, 1 H, enol), 2.61 (dd, J = 14.0, 2.4 Hz, 1 H, ketone), 2.55 (dd, J =
18.1, 3.0 Hz, 1 H, enol), 2.39 (t, J = 13.2 Hz, 1 H, ketone), 2.31 (s, 3 H,
enol), 2.29 (s, 3 H, ketone), 2.17 (ddd, J = 13.6, 6.3, 3.1 Hz, 1 H, enol),
2.07–2.13 (m, 4 H, ketone), 1.91 (dd, J = 13.4, 11.0 Hz, 1 H, enol), 1.75
(s, 3 H, enol).
HRMS (ESI): m/z [M + H]+ calcd for C16H12ClOS: 287.0297; found:
287.0286.
3m8d
Yellow oil, from substrate 2n [prepared by the Cu(ClO4)2·6H2O-cata-
lyzed Michael reaction of 1n, see below]; yield: 57.9 mg (63%).
1H NMR (300 MHz, CDCl3):  = 7.54 (d, J = 7.0 Hz, 2 H), 7.40 (t, J = 7.3
Hz, 2 H), 7.33 (tt, J = 7.2, 1.4 Hz, 1 H), 6.98 (s, 1 H), 6.86 (s, 1 H), 6.64 (s,
1 H), 5.04 (br s, 1 H), 2.35 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 155.9, 142.9, 141.0, 140.2, 128.8, 127.5,
127.2, 120.8, 115.1, 111.4, 21.6.
13C NMR (125 MHz, CDCl3):  = 205.9, 205.6, 200.6, 180.4, 162.6,
162.2, 148.2, 147.8, 143.8, 138.5, 137.54, 137.46, 136.9, 136.0, 129.8,
129.7, 127.2, 127.1, 122.8, 122.7, 118.9, 118.7, 110.4, 76.1, 71.8, 69.1,
53.6, 46.8, 46.0, 45.0, 42.1, 39.5, 30.1, 27.2, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C20H22NO3: 324.1600; found:
324.1596.
Reaction of 1p with Acetylacetone and the Subsequent I2-Mediat-
ed Phenol Formation
Step 1: A big tube (∅ 18 × 150 mm) was charged with enone 1p (5
mmol), acetylacetone (750 mg, 7.5 mmol), DBU (114 mg, 0.75 mmol),
and DMSO (5 mL). The reaction mixture was stirred at rt until the
4r/5r
Mixture of 4r:5r (1.25:1); white solid; yield: 0.950 g (50%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

J
C.-B. Miao et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3):  = 16.28 (s, 1 H, enol), 7.14–7.52 (m, 20 H,
ketone + enol), 4.51 (d, J = 2.8 Hz, 1 H, ketone), 4.29 (d, J = 10.6 Hz, 1 H,
enol), 4.19 (t, J = 12.1 Hz, 1 H, ketone), 4.14 (d, J = 2.5 Hz, 1 H, enol),
3.95 (d, J = 12.4 Hz, 1 H, ketone), 3.56–3.75 (m, 2 H, enol), 3.60 (d, J =
12.0 Hz, 1 H, ketone), 3.45–3.56 (m, 2 H, ketone), 3.09 (d, J = 10.6 Hz, 1
H, enol), 2.87–2.98 (m, 1 H, enol), 2.86 (dd, J = 14.7, 2.8 Hz, 1 H, ke-
tone), 2.76 (d, J = 14.6 Hz, 1 H, ketone), 2.69 (d, J = 18.6 Hz, 1 H, enol),
2.10 (s, 3 H, ketone), 1.69 (s, 3 H, enol), 0.63 (t, J = 7.1 Hz, 3 H, enol),
0.51 (t, J = 7.1 Hz, 3 H, ketone).
1H NMR (300 MHz, CDCl3):  = 7.80 (d, J = 7.2 Hz, 2 H), 7.55 (tt, J = 7.3,
1.2 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.10 (d, J = 8.2 Hz, 2 H), 7.05 (d, J =
8.1 Hz, 2 H), 4.43 (d, J = 11.1 Hz, 1 H), 4.06 (dd, J = 11.1, 6.0 Hz, 1 H),
3.86 (quint, J = 6.7 Hz, 1 H), 2.26 (s, 3 H), 2.19 (s, 3 H), 1.74 (s, 3 H),
1.11 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 203.3, 203.2, 203.1, 137.2, 137.0, 136.6,
133.1, 129.4, 129.1, 128.8, 128.2, 72.3, 46.4, 45.2, 30.6, 28.0, 21.1,
14.7.
HRMS (ESI): m/z [M + H]+ calcd for C22H25O3: 337.1804; found:
337.1810.
HRMS (ESI): m/z [M + H]+ calcd for C23H25O5: 381.1702; found:
381.1698.
2s′
3q
Yellow oil; yield: 0.445 g (28%).
White solid; yield: 114.8 mg (88%); mp 98–99 °C.
1H NMR (500 MHz, CDCl3):  = 16.39 (s, 1 H), 7.26–7.36 (m, 5 H), 7.11
(d, J = 8.0 Hz, 2 H), 7.05 (d, J = 7.9 Hz, 2 H), 6.42 (s, 1 H), 3.81 (s, 1 H),
3.17 (q, J = 7.0 Hz, 1 H), 2.27 (s, 3 H), 2.01 (s, 3 H), 1.30 (d, J = 7.1 Hz, 3
H).
13C NMR (125 MHz, CDCl3):  = 193.5, 179.4, 157.3, 140.5, 137.9,
136.4, 129.6, 129.4, 128.8, 127.1, 126.4, 120.6, 104.9, 46.2, 41.3, 23.1,
21.5, 21.0.
1H NMR (300 MHz, DMSO-d6):  = 9.72 (s, 1 H), 8.67 (ddd, J = 4.7, 1.7,
0.8 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.87 (td, J = 7.7, 1.8 Hz, 1 H), 7.74
(t, J = 1.5 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 2 H), 7.50 (dd, J = 2.2, 1.6 Hz, 1 H),
7.35 (ddd, J = 7.4, 4.8, 1.0 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 2 H), 7.08 (dd, J =
2.2, 1.7 Hz, 1 H), 2.35 (s, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 158.3, 156.0, 149.5, 142.0, 140.6,
137.4, 137.2, 136.9, 129.5, 126.6, 122.7, 120.5, 115.8, 114.1, 112.4,
20.7.
HRMS (ESI): m/z [M + H]+ calcd for C22H23O2: 319.1698; found:
319.1692.
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO: 262.1232; found:
262.1235.
3s
Yellow oil; yield: 75.1 mg (55%).
1H NMR (300 MHz, CDCl3):  = 7.28–7.44 (m, 5 H), 7.17–7.27 (m, 4 H),
6.72 (s, 2 H), 4.94 (br s, 1 H), 2.39 (s, 3 H), 2.01 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 152.7, 144.2, 142.3, 139.3, 136.7, 129.3,
129.2, 128.9, 128.2, 127.0, 125.4, 116.1, 115.9, 21.3, 18.0.
HRMS (ESI): m/z [M + H]+ calcd for C20H19O: 275.1436; found:
275.1440.
3r10c
White solid; yield: 147.9 mg (93%).
1H NMR (300 MHz, CDCl3):  = 7.32–7.40 (m, 10 H), 6.80 (s, 2 H), 5.28
(br s, 1 H), 3.82 (q, J = 7.1 Hz, 2 H), 0.77 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 170.2, 156.3, 142.8, 140.5, 128.4, 128.3,
127.7, 125.5, 115.9, 61.2, 13.5.
Cu(ClO4)2·6H2O-Catalyzed Michael Reaction of 1n/1s with Acetylac-
etone for the Preparation of 2n, 2s, and 2s′ and the Subsequent I2-
Mediated Phenol Formation
Reaction of 1,5-Diarylpenta-1,4-dien-3-ones 6 with Acetylacetone
and the Subsequent I2-Mediated Preparation of Hydroxylated Stil-
bene Derivatives 10
Step 1: A big tube (∅ 18 × 150 mm) tube was charged with enone
1n/1s (5 mmol), acetylacetone (750 mg, 7.5 mmol), Cu(ClO4)2·6H2O
(740 mg, 2 mmol), and THF (4 mL). The mixture was stirred (for 1n, at
rt; for 1s, at 80 °C) until the completion of reaction as determined by
TLC. H2O (10 mL) was added and the mixture was extracted with EtO-
Ac (3 × 25 mL). The combined organic phases were dried (anhyd
Na2SO4) and evaporated. The residue was purified by column chroma-
tography on silica gel eluting with EtOAc/PE to provide the corre-
sponding products of 2n, 2s, and 2s′.
Step 1: A big tube (∅ 18 × 150 mm) was charged with enone 6 (5
mmol), acetylacetone (750 mg, 7.5 mmol), DBU (114 mg, 0.75 mmol),
and DMSO (4–15 mL). Upon completion of the reaction as determined
by TLC, the reaction mixture was diluted with EtOAc and then succes-
sively washed with 1 N HCl, sat. aq NaHCO3, and brine. The organic
phase was dried (anhyd Na2SO4) and evaporated. The residue was pu-
rified by column chromatography on silica gel eluting with EtOAc/PE
to provide the corresponding products 7, 8, and 9 as a mixture (7c,
the second fraction; 8c the first fraction; 9c, the third fraction; 8c and
9c were hard to separate on silica gel column due to the tautomeriza-
tion. Recrystallization of the fraction 8c or 9c from EtOH 2–3 times
gave the single pure product).
Step 2: The process for the subsequent I2-mediated phenol formation
was the same as Step 2 in the general procedure for the preparation of
3a–g.
Step 2: The process for the subsequent I2-mediated phenol formation
of 10 (a mixture of 7, 8, and 9 was used) was the same as Step 2 in the
general procedure for the preparation of 3a–g.
2n16
White solid; yield: 1.070 g (87%).
1H NMR (300 MHz, CDCl3):  = 7.27–7.32 (m, 1 H), 7.16–7.27 (m, 4 H),
4.19 (d, J = 11.1 Hz, 1 H), 4.01 (ddd, J = 13.3, 8.8, 4.5 Hz, 1 H), 2.78 (dd,
J = 16.3, 8.8 Hz, 1 H), 2.65 (dd, J = 16.3, 4.4 Hz, 1 H), 2.24 (s, 3 H), 1.97
(s, 3 H), 1.86 (s, 3 H).
7c
White solid; yield: 0.833 g (46%); mp 128–129 °C.
1H NMR (500 MHz, CDCl3):  = 7.38 (d, J = 16.2 Hz, 1 H), 7.36 (d, J = 8.1
Hz, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 8.1 Hz, 2 H), 7.06 (d, J = 8.0
Hz, 2 H), 6.50 (d, J = 16.2 Hz, 1 H), 4.27 (d, J = 11.1 Hz, 1 H), 4.09 (ddd,
J = 11.1, 9.3, 4.1 Hz, 1 H), 2.94 (dd, J = 15.5, 9.2 Hz, 1 H), 2.85 (dd, J =
15.4, 4.2 Hz, 1 H), 2.36 (s, 3 H), 2.29 (s, 3 H), 2.25 (s, 3 H), 1.89 (s, 3 H).
2s
White solid; yield: 0.655 g (39%); mp 110–111 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

K
C.-B. Miao et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3):  = 203.6, 203.3, 197.9, 143.4, 141.2,
137.2, 137.0, 131.7, 129.8, 129.6, 128.5, 128.1, 125.2, 74.5, 45.4, 41.2,
30.1, 29.9, 21.6, 21.1.
13C NMR (75 MHz, CDCl3):  = 156.1, 143.2, 139.6, 137.82, 137.76,
137.5, 134.4, 129.52, 129.47, 129.4, 127.3, 127.0, 126.6, 118.4, 113.2,
111.5, 21.3, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H27O3: 363.1960; found:
HRMS (ESI): m/z [M + H]+ calcd for C22H21O: 301.1592; found:
363.1952.
301.1590.
8c/9c
10d
Mixture of 8c:9c (1:2.3); white solid; yield: 0.760 g (42%).
Yellow solid; yield: 124.1 mg (73%); mp 128–129 °C.
1H NMR (500 MHz, CDCl3):  = 16.31 (s, 1 H, enol), 7.25 (d, J = 8.0 Hz, 2
H, ketone), 7.21 (d, J = 8.1 Hz, 2 H, enol), 7.04–7.17 (m, 12 H, ketone +
enol), 6.60 (d, J = 16.1 Hz, 1 H, ketone), 6.59 (d, J = 16.1 Hz, 1 H, enol),
6.26 (d, J = 16.1 Hz, 1 H, ketone), 6.17 (d, J = 16.1 Hz, 1 H, enol), 4.04
(dd, J = 10.3, 6.7 Hz, 1 H, enol), 3.91 (td, J = 11.9, 5.0 Hz, 1 H, ketone),
3.76 (d, J = 12.4 Hz, 1 H, ketone), 2.83 (d, J = 18.3 Hz, 1 H, enol), 2.80
(d, J = 14.2 Hz, 1 H, ketone), 2.63 (dd, J = 14.2, 1.9 Hz, 1 H, ketone), 2.55
(dd, J = 18.3, 2.9 Hz, 1 H, enol), 2.33 (s, 3 H, ketone), 2.322 (s, 3 H,
enol), 2.317 (s, 3 H, enol), 2.33 (s, 3 H, ketone), 2.30 (s, 3 H, ketone),
2.23–2.37 (m, 2 H, ketone + enol), 2.06 (s, 3 H, ketone), 1.82 (br, 1 H,
enol), 1.74 (s, 3 H, enol), 1.65–1.73 (m, 2 H, ketone + enol).
13C NMR (125 MHz, CDCl3):  = 205.8 (ketone), 205.4 (ketone), 200.8
(enol), 179.8 (enol), 143.5, 138.4, 138.2, 137.9, 137.0, 136.1, 133.5,
133.2, 129.8, 129.8, 129.6, 129.5, 129.4, 128.6, 128.4, 127.2, 126.6,
126.5, 110.0, 75.2, 70.9, 68.9, 53.0, 45.9, 45.1, 44.0, 41.7, 39.0, 30.4,
29.8, 27.1, 21.31, 21.29, 21.11, 21.09.
1H NMR (300 MHz, DMSO-d6):  = 9.69 (s, 1 H), 7.68 (d, J = 8.6 Hz, 2
H), 7.65 (d, J = 8.6 Hz, 2 H), 7.52 (d, J = 8.6 Hz, 2 H), 7.44 (d, J = 8.6 Hz,
2 H), 7.35 (t, J = 1.5 Hz, 1 H), 7.28 (s, 2 H), 7.00 (t, J = 1.6 Hz, 1 H), 6.95
(t, J = 1.6 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6):  = 158.2, 140.6, 139.0, 138.8, 136.0,
132.4, 132.0, 129.3, 128.9, 128.7, 128.5, 128.2, 127.5, 116.2, 113.3,
112.8.
HRMS (ESI): m/z [M + H]+ calcd for C20H15Cl2O: 341.0500; found:
341.0497.
Reaction of 1,5-Diarylpenta-2,4-dien-1-ones 11 with Acetylace-
tone and the Subsequent I2-Mediated Preparation of Hydroxylated
Stilbene Derivatives 15
Step 1: A big tube (∅ 18 × 150 mm) was charged with enone 11 (5
mmol), acetylacetone (750 mg, 7.5 mmol), DBU (114 mg, 0.75 mmol),
and DMSO (4–15 mL). The reaction mixture was diluted with EtOAc
and then washed successively with 1 N HCl, sat. aq NaHCO3, and
brine. The organic phase was dried (anhyd Na2SO4) and evaporated.
The residue was purified by column chromatography on silica gel
eluting with EtOAc/PE to provide the corresponding products 12, 13,
and 14 as a mixture (12a, the second fraction; 13a the first fraction;
14a, the third fraction).
HRMS (ESI): m/z [M + H]+ calcd for C24H27O3: 363.1960; found:
363.1956.
10a
Yellow oil; yield: 96.6 mg (71%).
1H NMR (300 MHz, CDCl3):  = 7.59 (d, J = 7.0 Hz, 2 H), 7.51 (d, J = 7.2
Hz, 2 H), 7.43 (t, J = 7.3 Hz, 2 H), 7.32–7.39 (m, 3 H), 7.30 (t, J = 1.5 Hz,
1 H), 7.26 (t, J = 7.2 Hz, 1 H), 7.13 (d, J = 16.4 Hz, 1 H), 7.07 (d, J = 16.3
Hz, 1 H), 6.94–6.99 (m, 2 H), 5.20 (br s, 1 H).
Step 2: The process for the subsequent I2-mediated phenol formation
of 15 (a mixture of 12, 13, and 14 was used) was the same as Step 2 in
the general procedure for the preparation of 3a–g.
13C NMR (75 MHz, CDCl3):  = 156.2, 143.4, 140.8, 139.5, 137.2, 129.6,
128.9, 128.8, 128.3, 127.9, 127.7, 127.3, 126.7, 118.7, 113.7, 112.0.
12a
HRMS (ESI): m/z [M + H]+ calcd for C20H17O: 273.1279; found:
White solid; yield: 0.515 g (31%); mp 133–134 °C.
1H NMR (300 MHz, CDCl3):  = 7.93 (d, J = 7.2 Hz, 2 H), 7.56 (tt, J = 7.4,
1.2 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.10–7.32 (m, 5 H), 6.44 (d, J =
16.0 Hz, 1 H), 6.14 (dd, J = 15.9, 9.3 Hz, 1 H), 4.16 (d, J = 9.0 Hz, 1 H),
3.60–3.80 (m, 1 H), 3.07–3.25 (m, 2 H), 2.26 (s, 3 H), 2.17 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 203.7, 198.3, 136.9, 136.6, 133.4,
132.9, 128.8, 128.6, 128.4, 128.2, 127.8, 126.5, 71.9, 41.5, 39.0, 30.5,
30.2.
273.1273.
10b
Brown solid; yield: 131.1 mg (79%); mp 100–101 °C.
1H NMR (300 MHz, CDCl3):  = 7.49 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.7
Hz, 2 H), 7.21 (t, J = 1.3 Hz, 1 H), 7.03 (d, J = 16.3 Hz, 1 H), 6.83–6.97
(m, 7 H), 5.85 (br s, 1 H), 3.81 (s, 3 H), 3.79 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 159.3, 159.2, 156.2, 142.7, 139.7, 133.3,
130.1, 128.9, 128.2, 127.9, 126.3, 117.9, 114.3, 114.2, 112.9, 111.2,
55.44, 55.42.
HRMS (ESI): m/z [M + H]+ calcd for C22H23O3: 335.1647; found:
335.1641.
13a + 14a
HRMS (ESI): m/z [M + H]+ calcd for C22H21O3: 333.1491; found:
Mixture of 13a:14a (1.08:1); white solid; yield: 0.668 g (40%).
HRMS (ESI): m/z [M + H]+ calcd for C22H23O3: 335.1647; found:
333.1497.
335.1650.
10c
Pale pink solid; yield: 112.5 mg (75%); mp 121–122 °C.
15b
1H NMR (300 MHz, CDCl3):  = 7.50 (d, J = 8.1 Hz, 2 H), 7.42 (d, J = 8.1
Hz, 2 H), 7.28 (t, J = 1.5 Hz, 1 H), 7.25 (d, J = 8.1 Hz, 2 H), 7.18 (d, J = 8.0
Hz, 2 H), 7.12 (d, J = 16.4 Hz, 1 H), 7.07 (d, J = 16.4 Hz, 1 H), 6.92–6.97
(m, 2 H), 4.99 (br s, 1 H), 2.40 (s, 3 H), 2.37 (s, 3 H).
Yellow solid; yield: 35.7 mg (25%); mp 110–111 °C.
1H NMR (300 MHz, CDCl3):  = 7.46–7.55 (m, 4 H), 7.36 (t, J = 7.4 Hz, 2
H), 7.21–7.31 (m, 4 H), 7.14 (d, J = 16.4 Hz, 1 H), 7.08 (d, J = 16.4 Hz, 1
H), 6.93–6.99 (m, 2 H), 5.15 (s, 1 H), 2.40 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

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C.-B. Miao et al.
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13C NMR (75 MHz, CDCl3):  = 156.3, 143.3, 139.4, 137.9, 137.6, 137.3,
129.6, 129.5, 128.8, 128.4, 127.9, 127.1, 126.7, 118.5, 113.5, 111.7,
21.3.
13C NMR (75 MHz, CDCl3):  = 159.5, 156.3, 143.4, 140.9, 139.9, 130.1,
129.1, 128.9, 128.0, 127.7, 127.3, 126.3, 118.5, 114.3, 113.3, 111.7,
55.5.
HRMS (ESI): m/z [M + H]+ calcd for C21H19O: 287.1436; found:
HRMS (ESI): m/z [M + H]+ calcd for C21H19O2: 303.1385; found:
287.1428.
303.1381.
15c
Reaction of 16, 19, 21, and 23 with Acetylacetone and the Subse-
quent I2-Mediated Preparation of Phenols
Yellow oil; yield: 48.2 mg (32%).
Step 1: A big tube (∅ 18 × 150 mm) was charged with enone 1a (1.04
g, 5 mmol), 16/19/21/23 (7.5 mmol), DBU (114 mg, 0.75 mmol), and
DMSO (5 mL). The mixture was stirred at rt (for 23, at 5 °C) until the
completion of reaction (TLC analysis). The reaction mixture was dilut-
ed with EtOAc and then washed successively with 1 N HCl, sat. aq
NaHCO3, and brine. The organic phase was dried (anhyd Na2SO4) and
evaporated. The residue was purified by column chromatography on
silica gel eluting with EtOAc/PE to provide the corresponding product
17, 20, 22, and 24 (compound 20, 22, or 24 was a mixture of two dias-
tereoisomers).
1H NMR (300 MHz, CDCl3):  = 7.47–7.55 (m, 4 H), 7.35 (t, J = 7.3 Hz, 2
H), 7.22–7.29 (m, 2 H), 7.10 (d, J = 1.7 Hz, 2 H), 6.90–7.00 (m, 4 H),
5.63 (br s, 1 H), 3.83 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 159.4, 156.4, 142.9, 139.4, 137.3, 133.3,
129.4, 128.8, 128.5, 128.3, 127.9, 126.7, 118.2, 114.3, 113.4, 111.4,
55.5.
HRMS (ESI): m/z [M + H]+ calcd for C21H19O2: 303.1385; found:
303.1380.
15d
Step 2: The process for the subsequent I2-mediated phenol formation
of 10 was the same as Step 2 in the general procedure for the prepara-
tion of 3a–g.
White solid; yield: 84.4 mg (55%); mp 136–137 °C.
1H NMR (300 MHz, CDCl3):  = 7.51 (d, J = 8.5 Hz, 4 H), 7.32–7.43 (m, 4
H), 7.21–7.32 (m, 2 H), 7.11 (d, J = 16.4 Hz, 1 H), 7.10 (d, J = 16.4 Hz, 1
H), 6.95 (dt, J = 21.9, 1.9 Hz, 2 H), 5.11 (s, 1 H).
17
13C NMR (75 MHz, CDCl3):  = 156.3, 142.1, 139.7, 139.2, 137.1, 133.8,
White solid; yield: 0.840 g (50%); mp 107–108 °C.
1H NMR (300 MHz, DMSO-d6):  = 7.51 (d, J = 7.4 Hz, 2 H), 7.31–7.39
(m, 4 H), 7.28 (t, J = 7.5 Hz, 2 H), 7.22 (t, J = 7.1 Hz, 1 H), 7.17 (t, J = 7.1
Hz, 1 H), 5.47 (d, J = 0.8 Hz, 1 H), 4.46 (d, J = 12.4 Hz, 1 H), 3.82 (td, J =
12.4, 3.8 Hz, 1 H), 3.33 (q, J = 6.6 Hz, 1 H), 2.59 (t, J = 13.1 Hz, 1 H), 2.36
(dq, J = 17.9, 7.2 Hz, 1 H), 2.19 (dq, J = 17.9, 7.2 Hz, 1 H), 1.86 (dd, J =
13.7, 3.9 Hz, 1 H), 0.77 (t, J = 7.3 Hz, 3 H), 0.63 (d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 208.7, 208.0, 146.8, 143.1, 128.5,
128.0, 127.3, 126.5, 126.4, 124.8, 78.6, 66.1, 52.7, 47.5, 41.5, 36.5, 7.9,
7.2.
129.8, 129.0, 128.9, 128.5, 128.1, 128.0, 126.7, 118.5, 113.5, 112.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H16ClO: 307.0890; found:
307.0879.
15e
Yellow solid; yield: 99.9 mg (63%); mp 156–157 °C.
1H NMR (300 MHz, DMSO-d6):  = 9.84 (s, 1 H), 8.32 (d, J = 9.0 Hz, 2
H), 7.96 (d, J = 9.0 Hz, 2 H), 7.64 (d, J = 7.2 Hz, 2 H), 7.48 (s, 1 H), 7.40
(t, J = 7.5 Hz, 2 H), 7.23–7.34 (m, 3 H), 7.09 (dt, J = 14.4, 1.7 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6):  = 158.3, 146.7, 139.6, 139.3, 136.9,
129.2, 128.8, 128.1, 127.9, 127.8, 126.6, 124.1, 116.6, 113.8, 113.5.
HRMS (ESI): m/z [M + H]+ calcd for C22H25O3: 337.1804; found:
337.1800.
HRMS (ESI): m/z [M + K]+ calcd for C20H15NO3K: 356.0689; found:
356.0693.
20
Mixture of two diastereoisomers, dr = 2:1; colorless oil; yield: 1.075 g
(58%).
HRMS (ESI): m/z [M + H]+ calcd for C25H23O3: 371.1647; found:
15f
Yellow solid; yield: 93.0 mg (53%); mp 85–86 °C.
371.1641.
1H NMR (500 MHz, CDCl3):  = 7.58 (d, J = 7.1 Hz, 2 H), 7.41–7.48 (m, 4
H), 7.31–7.40 (m, 3 H), 7.28 (t, J = 1.3 Hz, 1 H), 7.05 (d, J = 16.4 Hz, 1
H), 7.04 (d, J = 16.3 Hz, 1 H), 6.96 (dt, J = 7.9, 2.2 Hz, 2 H), 5.26 (s, 1 H).
13C NMR (125 MHz, CDCl3):  = 156.3, 143.5, 140.7, 139.1, 136.1,
131.9, 129.0, 128.9, 128.3, 128.2, 127.8, 127.2, 121.6, 118.7, 114.0,
112.0.
22
Mixture of two diastereoisomers, dr = 1.35:1; colorless oil; yield:
1.116 g (60%).
HRMS (ESI): m/z [M + H]+ calcd for C25H25O3: 373.1804; found:
373.1811.
HRMS (ESI): m/z [M + H]+ calcd for C20H16BrO: 351.0385; found:
351.0378.
2410b
Mixture of two diastereoisomers, dr = 1.25:1; white solid; yield:
1.437 g (85%).
15g
Yellow oil; yield: 61.9 mg (41%).
1H NMR (500 MHz, CDCl3):  = 7.59 (d, J = 7.1 Hz, 2 H), 7.41–7.46 (m, 4
H), 7.35 (tt, J = 7.3, 1.1 Hz, 1 H), 7.26–7.29 (m, 1 H), 7.08 (d, J = 16.2 Hz,
1 H), 6.92–6.98 (m, 3 H), 6.90 (d, J = 8.8 Hz, 2 H), 5.22 (br s, 1 H), 3.82
(s, 3 H).
188d
White solid; yield: 110.5 mg (85%).
1H NMR (300 MHz, CDCl3):  = 7.58 (d, J = 7.1 Hz, 2 H), 7.29–7.46 (m, 8
H), 7.08 (dd, J = 20.6, 1.7 Hz, 2 H), 4.89 (s, 1 H), 2.19 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 154.4, 144.2, 141.7, 140.6, 139.6, 129.4,
128.9, 128.2, 127.4, 127.13, 127.07, 121.5, 120.9, 112.6, 13.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N

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25
2016, 7, 3147. (d) Viswanadh, N.; Ghotekar, G. S.; Thoke, M. B.;
Velayudham, R.; Shaikh, A. C.; Karthikeyan, M.; Muthukrishnan,
M. Chem. Commun. 2018, 54, 2252. (e) Olah, G. A.; Ernst, T. D. J.
Org. Chem. 1989, 54, 1204. (f) Yang, L.; Huang, Z.; Li, G.; Zhang,
W.; Cao, R.; Wang, C.; Xiao, J.; Xue, D. Angew. Chem. Int. Ed.
2018, 57, 1968. (g) Ding, G.; Han, H.; Jiang, T.; Wu, T.; Han, B.
Chem. Commun. 2014, 50, 9072. (h) Wu, Z.; Glaser, R. J. Am.
Chem. Soc. 2004, 126, 10632. (i) Soledade, M.; Pedras, C.; Suchy,
M. Bioorg. Med. Chem. 2006, 14, 714.
Colorless oil; yield: 47.4 mg (28%).
1H NMR (300 MHz, CDCl3):  = 8.09 (d, J = 7.1 Hz, 2 H), 7.62 (tt, J = 7.4,
1.3 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.31–7.46 (m, 3 H), 7.31 (s, 1 H),
7.27–7.30 (m, 1 H), 4.19 (d, J = 7.7 Hz, 1 H), 4.00 (q, J = 7.1 Hz, 2 H),
3.89 (d, J = 7.7 Hz, 1 H), 2.33 (s, 3 H), 0.98 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 198.6, 193.9, 166.6, 136.7, 133.9, 133.7,
129.0, 128.7, 128.5, 127.8, 62.2, 52.2, 37.1, 36.5, 29.9, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C21H21O4: 337.1440; found:
337.1436.
(3) (a) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E.
Angew. Chem. Int. Ed. 2003, 42, 112. (b) Lee, D.-H.; Kwon, K.-H.;
Yi, C. S. J. Am. Chem. Soc. 2012, 134, 7325. (c) Schmidt, B.;
Riemer, M. J. Org. Chem. 2014, 79, 4104.
Compound 35
(4) (a) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1672.
(b) Chow, K.; Moore, H. W. Tetrahedron Lett. 1987, 28, 5013.
(c) Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F.
J. Am. Chem. Soc. 1990, 112, 3093. (d) Huffman, M. A.;
Liebeskind, L. S. J. Am. Chem. Soc. 1990, 112, 8617. (e) Huffman,
M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1991, 113, 2771.
(f) Collomb, D.; Doutheau, A. Tetrahedron Lett. 1997, 38, 1397.
(g) Serra, S.; Fuganti, C.; Brenna, E. Chem. Eur. J. 2007, 13, 6782.
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Miehlich, B.; Frey, W.; Bats, J. W. Chem. Eur. J. 2006, 12, 5806.
(b) Chen, Y.; Yan, W.; Akhmedov, N. G.; Shi, X. Org. Lett. 2010,
12, 344. (c) Teo, W. T.; Rao, W.; Ng, C. J. H.; Koh, S. W. Y.; Chan, P.
W. H. Org. Lett. 2014, 16, 1248.
Compound 35 was prepared according to the reported procedure.7
Compound 36
A mixture of chalcone 1a (1.04 g, 5 mmol), acetylacetone (0.55 g, 5.5
mmol), and NaOH (40 mg, 1 mmol) in a mixed solvent of EtOH and
H2O (20 mL, EtOH/H2O = 4:1) was heated at 80 °C for 24 h. Upon cool-
ing to 10 °C, a yellow solid precipitated out. After filtering, washing
with the mixed solvent of EtOH and H2O (EtOH/H2O = 7:3), and dry-
ing, compound 36 was obtained as yellow solid; yield: 0.725 g (50%);
mp 127–128 °C.
1H NMR (300 MHz, CDCl3):  = 16.42 (s, 1 H), 7.28–7.46 (m, 6 H),
7.22–7.28 (m, 3 H), 7.14–7.22 (m, 1 H), 6.50 (d, J = 2.8 Hz, 1 H), 4.14
(dd, J = 8.3, 1.6 Hz, 1 H), 3.31 (ddd, J = 17.2, 8.3, 2.8 Hz, 1 H), 3.03 (dd,
J = 17.2, 1.7 Hz, 1 H), 2.00 (s, 3 H).
(6) (a) Li, C.; Zeng, Y.; Zhang, H.; Feng, J.; Zhang, Y.; Wang, J. Angew.
Chem. Int. Ed. 2010, 49, 6413. (b) Bamfield, P.; Gordon, P. F.
Chem. Soc. Rev. 1984, 13, 441.
(7) Stalling, T.; Harker, W. R. R.; Auvinet, A.-L.; Cornel, E. J.; Harrity,
J. P. A. Chem. Eur. J. 2015, 21, 2701.
13C NMR (75 MHz, CDCl3):  = 192.7, 180.1, 151.0, 143.7, 138.8, 129.7,
128.8, 128.7, 127.3, 126.9, 126.1, 122.1, 106.3, 38.4, 36.1, 23.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H19O2: 291.1385; found:
291.1376.
(8) (a) Eichinger, K.; Nussbaumer, P.; Balkan, S.; Schulz, G. Synthesis
1987, 1061. (b) Katritzky, A. R.; Belyakov, S. A.; Fang, Y.; Kiely, J.
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Yi, W.; Huang, X.; Miao, Y.; Zhang, J.; Cai, C.; Zhang, W. Org. Lett.
2015, 17, 1090. (e) Poudel, T. N.; Lee, Y. R. Chem. Sci. 2015, 6,
7028. (f) Hu, Z.; Dong, J.; Men, Y.; Li, Y.; Xu, X. Chem. Commun.
2017, 53, 1739. (g) Maezono, S. M. B.; Poudel, T. N.; Lee, Y. R.
Org. Biomol. Chem. 2017, 15, 2052.
(9) (a) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209.
(b) Izawa, Y.; Zheng, C.; Stahl, S. S. Angew. Chem. Int. Ed. 2013,
52, 3672. (c) Pun, D.; Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2013,
135, 8213. (d) Zhang, J.; Jiang, Q.; Yang, D.; Zhao, X.; Dong, Y.;
Liu, R. Chem. Sci. 2015, 6, 4674. (e) Zhang, Z.; Hashiguchi, T.;
Ishida, T.; Hamasaki, A.; Honma, T.; Ohashi, H.; Yokoyama, T.;
Tokunaga, M. Org. Chem. Front. 2015, 2, 654. (f) Poudel, T. N.;
Lee, Y. R. Org. Lett. 2015, 17, 2050.
Funding Information
We are grateful for the financial support from Natural Science Foun-
dation of Jiangsu Province (BK20181462), the Jiangsu Key Laboratory
of Advanced Catalytic Materials and Technology (BM2012110), and
the Advanced Catalysis and Green Manufacturing Collaborative Inno-
vation Center.
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Supporting information for this article is available online at
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(10) (a) Liang, Y.-F.; Li, X.; Wang, X.; Zou, M.; Tang, C.; Liang, Y.; Song,
S.; Jiao, N. J. Am. Chem. Soc. 2016, 138, 12271. (b) Liang, Y.-F.;
Song, S.; Ai, L.; Li, X.; Jiao, N. Green Chem. 2016, 18, 6462.
(c) Wang, S.-K.; Chen, M.-T.; Zhao, D.-Y.; You, X.; Luo, Q.-L. Adv.
Synth. Catal. 2016, 358, 4093.
(11) (a) Miao, C.-B.; Zhang, M.; Tian, Z.-Y.; Xi, H.-T.; Sun, X.-Q.; Yang,
H.-T. J. Org. Chem. 2011, 76, 9809. (b) Miao, C.-B.; Dong, C.-P.;
Zhang, M.; Ren, W.-L.; Meng, Q.; Sun, X.-Q.; Yang, H.-T. J. Org.
Chem. 2013, 78, 4329. (c) Miao, C.-B.; Liu, R.; Sun, Y.-F.; Sun, X.-
Q.; Yang, H.-T. Tetrahedron Lett. 2017, 58, 541. (d) Li, Y.; Xu, H.;
Xing, M.; Huang, F.; Ji, J.; Gao, J. Org. Lett. 2015, 17, 3690.
(12) (a) Miao, C.-B.; Wang, Y.-H.; Xing, M.-L.; Lu, X.-W.; Sun, X.-Q.;
Yang, H.-T. J. Org. Chem. 2013, 78, 11584. (b) Miao, C.-B.; Sun, Y.-
F.; Wu, H.; Sun, X.-Q.; Yang, H.-T. Adv. Synth. Catal. 2018, 360,
2440.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–N