Collective Syntheses of 2-(3-Methylbenzofuran-2-yl)phenol-Derived Natural Products by a Cascade [3,3]-Sigmatropic Rearrangement/Aromatization Strategy

Article abstract of DOI:10.1021/acs.joc.7b02066

A cascade [3,3]-sigmatropic rearrangement/aromatization strategy to the synthesis of 2-(3-methylbenzofuran-2-yl)phenol derivatives was developed and applied to the collective syntheses of seven 2-arylbenzofuran-containing natural products, namely glycybenzofuran, glycyuralin E, lespedezol A₁, puerariafuran, 7,2′,4′-trihydroxy-3-benzofurancarboxylic acid, coumestrol, and 4′-O-methylcoumestrol. Among them, the total syntheses of glycybenzofuran, glycyuralin E, puerariafuran, 7,2′,4′-trihydroxy-3-benzofurancarboxylic acid, and 4′-O-methylcoumestrol were reported for the first time. The practicality of this novel strategy in preparation of the key intermediates was demonstrated by performing the reaction on gram scale and by synthesizing a series of natural products with 2-(3-methylbenzofuran-2-yl)phenol scaffolds in a common strategy.

Full text of DOI:10.1021/acs.joc.7b02066

Subscriber access provided by University at Buffalo Libraries
Article
Collective Syntheses of 2-(3-Methylbenzofuran-2-yl)
phenol Derived Natural Products by a Cascade [3,3]-
Sigmatropic Rearrangement/Aromatization Strategy
Yingzhan Tang, Chongguo Jiang, Xinhang Zhang, Chengjun Liu, Jingsheng Lin,
Yanshi Wang, Chuan Du, Xiaoshi Peng, Wei Li, Yongxiang Liu, and Maosheng Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02066 • Publication Date (Web): 25 Sep 2017
Downloaded from http://pubs.acs.org on September 25, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 12
The Journal of Organic Chemistry
1
2
3
4
5
6
Collective
Syntheses
of
7
8
9
2-(3-Methylbenzofuran-2-yl) phenol Derived Natural
Products by Cascade [3,3]-Sigmatropic
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rearrangement/Aromatization Strategy
Yingzhan Tang,a,b Chongguo Jiang,a,b Xinhang Zhang,a,b,c Chengjun Liu,a,b,c Jingsheng Lin,a,b,c
Yanshi Wang,a,b Chuan Du,a,b Xiaoshi Peng,a,b Wei Li,d Yongxiang Liu,*a,b,c and Maosheng
Cheng*a,b
a Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang
110016, P. R. China
b Institute of Drug Research in Medicine Capital of China, Benxi 117000, P. R. China
c Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
d Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan
ABSTRACT:
A cascade [3,3]-sigmatropic rearrangement/aromatization strategy to the synthesis of
2-(3-methylbenzofuran-2-yl)phenol derivatives was developed and applied to the collective syntheses of seven
2-arylbenzofuran-containing natural products, namely glycybenzofuran, glycyuralin E, lespedezol A1,
puerariafuran, 7,2',4'-trihydroxy-3-benzofurancarboxylic acid, coumestrol and 4’-O-methylcoumestrol. Among
them, the total syntheses of glycybenzofuran, glycyuralin E, puerariafuran, 7,2',4'-trihydroxy-
3-benzofurancarboxylic acid and 4'-O-methylcoumestrol were reported for the first time. The practicality of
this novel strategy in preparation of the key intermediates was demonstrated by performing at gram scales
and by synthesizing a series of natural products with 2-(3-methylbenzofuran-2-yl)phenol scaffolds in a
common strategy.
Introduction
2-Arylbenzofuran-containing natural products, isolated from botanical families1 such as the moraceae,1a-1b
asteraceae1c and leguminosae1d having attracted considerable attention for their extensive biological activities,2
including antitumor, antimicrobial, analgesic, anti-inflammatory and antiviral, contain a common scaffold
3c
2-(3-methylbenzofuran-2-yl)phenol. Many synthetic strategies to natural products like lespedezol A1 and
coumestrol3f (Scheme 1a), with methyl group oxidation state modification in the 3-position of arylbenzofuran
moiety in this scaffold, have been developed,4 including construction of furan rings4c-4d,4f and directed arylation
by carbon-carbon bond formation. 4a-4b,4e,4g,4i In this study, an unprecedent collective syntheses strategy, outlined
in Scheme 1, was reported including the syntheses of glycybenzofuran (3-methyl),3e
7,2',4'-trihydroxy-3-benzofurancarboxylic acid (3-carboxy),3a coumestrol,3f 4'-O-methylcoumestrol (3-phenoxo),3b
lespedezol A1 (3-phenoxymethyl),3c glycyuralin E (3-hydroxymethyl)3g and puerariafuran (3-formyl),3d some
overcoming previous cumbersome and individual strategies.
Results and Discussion
Inspired by the similarities in structures of these natural products, we proposed a highly atom-economical
transformation involving a cascade [3,3]-sigmatropic rearrangement/aromatization synthetic strategy to the
2-(3-methylbenzofuran-2-yl)phenol framework, which would afford the general structural motifs for the
collective syntheses of a number of 2-arylbenzofuran type natural products via the SeO2-mediated oxidation of
the methyl groups5 and some manipulations of functional groups (Scheme 1b). Strategically, the γ,δ-unsaturated
ketone intermediate A, prone to isomerizing to the 2-(3-methylbenzofuran-2-yl)phenol driven by aromatization
once upon formation, could be generated from the 3-(phenoxymethyl)benzofuran substrate B via a
[3,3]-sigmatropic rearrangement.6 The precursor B can be facilely prepared from an etherification of
benzofuran-3-ylmethanol C and phenol D by a Mitsunobu reaction.7
Scheme 1. 2-(3-Methylbenzofuran-2-yl)phenol derived natural products and our proposed common synthetic
strategy
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To test the feasibility of this [3,3]-sigmatropic rearrangement/aromatization reaction, an ether precursor 1 was
used, synthesized by Mitsunobu reaction from two readily available fragments (See Supporting information for
the detailed synthetic route).8 The synthesized substrate 1 was heated to 180 °C under the neat conditions for 8
h, as expected, the desired product 2 was engendered with an isolated yield of 56% (Table 1, entry 1); while
lower yield (32%) was obtained by using the same temperature and mesitylene as solvent (Table 1, entry 2). To
our delight, when the substrate was dispersed in a quantitative amount of silica gel, the temperature could be
decreased to 140 °C and the reaction time shortened to 4 h without compromising, even better, in yield (75%)
(Table 1, entry 3). Further attempts on lowering reaction temperature with the use of silica gel proved
unsuccessful (Table 1, entries 4 and 5). In the examination of catalytic amount of Lewis acids such as InF3, ZnCl2
and SnCl2 relatively
Table 1. Screening of [3,3]-sigmatropic rearrangement/aromatization conditions of
substrate 1
entry
solvent
T (°C)
180
180
140
120
100
140
140
140
20
additive
-
t (h)
8
yield (%)a
56
1
2
-
mesitylene
-
-
8
32
3
silica gel
silica gel
silica gel
InF3
4
75b
38b
0b
4
-
4
5
-
4
6
toluene
toluene
toluene
toluene
toluene
4
0c
7
ZnCl2
SnCl2
4
38c
35c
40c
41c
8
4
9
TiCl4
4
10
20
BF3·Et2O
4
Note: aIsolated yields; b1.0 g silica gel was used for 1.0 mmol substrate;
cThe reaction was run at the catalysis of 10 mol % catalysts.
ACS Paragon Plus Environment

Page 3 of 12
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
lower yields and unidentified by-products were met (Table 1, entries 6-8). Catalytic amount of TiCl4 and BF3·Et2O
could prompt the [3,3]-sigmatropic rearrangement/aromatization to occur at room temperature; however,
relatively lower yields prevented the further applications of these catalysts (Table 1, entries 9-10). A similar result
was reported by Kim et al. as a side-reaction in the synthesis of pterocarpenes and coumestans.9 Finally, the
optimal conditions were determined as to heat the mixture of the substrate (1.0 mmol) and silica gel (1.0 g) at
140 °C under neat conditions for 4 h (Table 1, entry 3).
9
With the optimal conditions (Table 1, entry 3), the [3,3]-sigmatropic rearrangement/aromatization strategy
was assessed with the synthesis of glycybenzofuran. This metal free conditions allowed us to prepare the
2-(3-methylbenzofuran-2-yl)phenol 2 in gram scales, which assured the synthesis of the target natural product in
a large scale. After several functional group manipulations including O-methylation, deprotection of benzyl
groups and MOM protection of hydroxyl groups, the intermediate 5 was obtained in a moderate yield.
Bromination on the electron-rich phenyl ring of 5 afforded the precursor 6 in 35% yield,10 which could be purified
by the column chromatography to eliminate another major bromo-regioisomer by-product. After conducting a
palladium-catalyzed Suzuki coupling10 between the bromide precursor 6 and prenyl boronic ester11 and a CSA
promoted deprotection of MOM group, the total synthesis of glycybenzofuran 8 have been accomplished for the
first time via a 6-step sequence starting from the key intermediate 2-(3-methylbenzofuran-2-yl)phenol 2 (Scheme
2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Total synthesis of glycybenzofuran and glycyuralin E
Scheme 3. Total synthesis of coumestrol, 7, 2', 4'-trihydroxy-3-benzofurancarboxylic acid,
4'-O-methylcoumestrol and lespedezol A1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 12
1
2
3
4
5
6
7
8
9
With the collective synthesis concept based on the methyl oxidation state modification of
2-(3-methylbenzofuran-2-yl)phenol derivatives in mind, we intended to convert the key intermediate 7 in the
synthesis of glycybenzofuran to glycyuralin E 12 by a ring closure etherification and oxidation of methyl group
shown in Scheme 2. An acid-catalyzed deprotection of MOM and sequential cyclization of the intermediate 7
provided the chroman derivative 9 followed by a benzyl protection of phenol moiety to form the intermediate 10.
On treating with SeO2, intermediate 10 underwent a benzylic oxidation to deliver the aldehyde 11, which was
then exposed to a hydrogen atmosphere under the catalysis of Pd/C to reduce the aldehyde into alcohol and
remove the benzyl groups simultaneously, allowing for the first access to glycyuralin E 12 with an acceptable
yield in 8 steps from 2-(3-methylbenzofuran-2-yl)phenol 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the synthetic route to coumestrol 17 (Scheme 3), benzofuran-3-ylmethanol moiety 1a was coupled with
phenol 13 to afford the precursor 14 through Mitsunobu reaction, followed by a transformation into
2-(3-methylbenzofuran-2-yl)phenol 15 under the standard conditions. It was worth mentioning that the
lactonization was realized by a domino SeO2-mediated benzylic oxidation/hemiacetal formation and oxidation
one-pot sequence in a good yield. Full deprotection of methyl and benzyl ethers provided access to coumestrol
17 in 2 steps based on the key intermediate 15. A following hydrolysis of the lactone in coumestrol 17 under the
basic conditions has constructed 7,2',4'-trihydroxy-3-benzofurancarboxylic acid 18 in 75% yield in 3 steps based
on the same intermediate 15 for the first time.
Next, the synthetic strategy was further demonstrated by the syntheses of 4'-O-methylcoumestrol and
lespedezol A1. A selective deprotection of benzyl group in the intermediate 16 by BBr3 followed SeO2-meditated
oxidization/esterification protocol from intermediate 15 as shown in Scheme 3, thus, the 4'-O-methylcoumestrol
19 was synthesized in a yield of 80%. TBS protection of 4'-O-methylcoumestrol 19 provided the corresponding
silyl ether 20 in 95% yield, which was converted into lespedezol A1 21 after the reduction of lactone to ether. The
total syntheses of four natural products were achieved by a single intermediate 15 via several functional group
transformations.
Finally, the total synthesis of puerariafuran was conducted by
a Mitsunobu reaction using
benzofuran-3-ylmethanol 1a and 3-(benzyloxy)phenol 22 as the starting materials. The resulted ether 23 was
subjected to Claisen rearrangement/aromatization reaction conditions to generate the phenol 24. Protection of
the phenol 24 with methyl iodide followed by a SeO2-mediated benzylic oxidation gave the aldehyde 26, which
was treated with BBr3 to deprotect the benzyl group leading to the first total synthesis of puerariafuran 27 in 3
steps from the key intermediate 2-(3-methylbenzofuran-2-yl)phenol 24 (Scheme 4).
Scheme 4. Total synthesis of puerariafuran
Conclusion
In summary, a metal free thermally promoted [3,3]-sigmatropic rearrangement/aromatization strategy to the
synthesis of 2-(3-methylbenzofuran-2-yl)phenol derivatives based on the simple ether substrates has been
developed for the first time. The manipulations of methyl group led to the collective syntheses of a series of
natural products derived from 2-(3-methylbenzofuran-2-yl)phenol. This unprecedent strategy represents a highly
atom-economical process allowing facile preparation of seven 2-arylbenzofuran type natural products, in which,
five of them were synthesized for the first time. The collective syntheses of these natural products lay a solid
foundation for the further bioactive evaluation of 2-arylbenzofuran-containing natural products and their
derivatives.
Experimental Section
General Experimental Methods. Unless otherwise noted, reagents were obtained commercially and used
without further purification. Tetrahydrofuran (THF) was distilled from sodium under a nitrogen atmosphere.
ACS Paragon Plus Environment

Page 5 of 12
The Journal of Organic Chemistry
1
2
3
4
Dichloromethane (DCM) was distilled from calcium hydride under a nitrogen atmosphere. Toluene was distilled
from sodium under
a nitrogen atmosphere. TLC analysis of reaction mixtures was performed on
Dynamicadsorbents silica gel F-254 TLC plates. Flash chromatography was carried out on Zeoprep 60 (200-300
mesh) silica gel. 1H and 13C NMR spectra were recorded with Bruker Avance-III 600 spectrometers and referenced
to CDCl3, DMSO-d6 and CD3OD. HR-ESIMS was recorded on a Bruker micro-TOFQ-Q instrument. IR spectra were
recorded on a Bruker IFS 55 spectrometer. Melting points (Mp) were tested on Thomas Hoover capillary melting
point apparatus.
5
6
7
8
9
Experimental Procedures and Spectroscopic Data of the Synthesized Compounds
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6-(Benzyloxy)benzofuran-3-yl)methanol (1a). To a vigorously stirred solution of potassium carbonate (50 g,
0.36 mol) in water (400 mL) was added 2-(2-acetyl-5-(benzyloxy)phenoxy)acetic acid ethyl ester a5 (100 g, 0.3
mol) and the mixture was gently refluxed for 3 h. The solution was cooled to 5 °C and acidified carefully with a
solution of concentrated HCl. The deposited precipitate was filtered off, washed with cold water. The resulting
crude product and anhydrous sodium acetate (96 g, 1.2 mol) was dissolved in acetic anhydride (390 g, 2.8 mol)
and the mixture was heated at 160 °C for 3 h. After cooling, the mixture was poured into water (900 mL) and
then extracted with diethyl ether. The combined organic layers were washed with a saturated aqueous solution
of Na2CO3 and brine, dried over anhydrous Na2SO4, and then evaporated to dryness. The mixture of the dry crude
product and selenium dioxide (33 g, 0.3 mol) in dry 1,4-dioxane (200 mL) was refluxed for 48 h. The resulting
black precipitate was filtered off and the crude product was evaporated to dryness. To a stirred solution of the
crude mixture in methanol (100 mL) was added NaBH4 in small portions at room temperature until the entire
amount of the aldehyde was transformed. Then the reaction mixture was treated with 5 M HCl (10 mL). The
crude product was treated with a mixture of ethyl acetate and water (1:1, v/v). The organic layers were
separated, washed with water, brine and then dried over anhydrous Na2SO4, evaporated to dryness, purified by a
flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:5, Rf = 0.1) to give the product 1a
1
(48.0 g) as a yellow powder with a yield of 63%. Mp 126.6–127.1 °C; H NMR (600 MHz, CDCl3) δ 7.55 – 7.51 (m,
2H), 7.46 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.99 (dd, J =
8.5, 2.2 Hz, 1H), 5.11 (s, 2H), 4.80 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 157.5, 156.7, 141.6, 137.0, 128.8, 128.2,
127.6, 120.5, 120.4, 120.2, 112.7, 97.6, 70.7, 56.2; IR (thin film, cm-1) 3402, 3052, 2928, 2843, 1597, 1483, 1120;
HRMS (ESI) m/z [M+H]+ Calcd. for C16H15O3 255.1021, Found 255.1016.
6-(Benzyloxy)-3-((3,5-bis(benzyloxy)phenoxy)methyl)benzofuran (1). To a solution of (6-(benzyloxy)benzofuran-
3-yl)methanol 1a (2.0 g, 8 mmol), 3,5-dibenzyloxy phenol a3 (2.9 g, 9.6 mmol) and triphenylphosphine (3.2 g, 12
mmol) in dry THF was added diisopropyl azodiformate (2.4 g, 12 mmol) dropwise at 0 °C for 15 min under a
nitrogen atmosphere. The reaction was stirred at room temperature for 4 h. The crude mixture was evaporated
to dryness and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:50, Rf
1
= 0.3) to afford the product 1 (1.9 g) as a yellow oil with a yield of 45%. H NMR (600 MHz, CDCl3) δ 7.57 (s, 1H),
7.50 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.4 Hz, 2H), 7.37-7.43 (m, 4H), 7.39 (t, J = 7.5 Hz, 6H), 7.32-7.35 (m, 3H), 7.09
(d, J = 2.2 Hz, 1H), 6.99 (dd, J = 8.5, 2.2 Hz, 1H), 6.29 (s, 3H), 5.12 (s, 2H), 5.10 (s, 2H), 5.01 (s, 4H); 13C NMR (150
MHz, CDCl3) δ 160.8, 160.6, 157.6, 156.6, 142.5, 137.0, 136.9, 128.8, 128.7, 128.6, 128.2, 128.1, 127.7, 127.6,
127.4, 120.5, 120.3, 116.7, 112.9, 97.6, 95.2, 95.0, 70.7, 70.3, 61.5; IR (thin film, cm-1) 3430, 3031, 2873, 1624,
1599, 1454, 1378, 1164, 1134, 1058; HRMS (ESI) m/z [M+H]+ Calcd. for C36H31O5 543.2166, Found 543.2174.
3,5-Bis(benzyloxy)-2-(6-(benzyloxy)-3-methylbenzofuran-2-yl)phenol (2). To a solution of 6-(benzyloxy)-3-((3,5-
bis(benzyloxy)phenoxy)methyl)benzofuran 1 (1.0 g, 1.8 mmol) in DCM (10 mL) was added silica gel (2.0 g) and the
DCM was removed in vacuo. The mixture was heated at 140 °C for 4 h. The crude mixture was purified by a flash
column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.2) to afford the product 2 (713
1
mg) as a yellow oil with a yield of 73%. H NMR (600 MHz, CDCl3) δ 7.47 (dd, J = 7.9, 0.9 Hz, 2H), 7.44 – 7.42 (m,
2H), 7.41 – 7.38 (m, 5H), 7.36 – 7.32 (m, 2H), 7.29 – 7.27 (m, 3H), 7.26 – 7.23 (m, 2H), 7.09 (d, J = 2.1 Hz, 1H), 6.98
(dd, J = 8.5, 2.2 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 5.95 (s, 1H), 5.13 (s, 2H), 5.05 (s, 2H), 5.03
(s, 2H), 2.10 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.7, 158.6, 157.3, 156.7, 155.6, 143.9, 137.1, 136.8, 136.7,
128.8, 128.7, 128.6, 128.3, 128.1, 127.8, 127.7, 127.6, 127.1, 124.1, 119.7, 115.8, 112.2, 100.4, 97.3, 94.7, 94.2,
70.8, 70.6, 70.3, 9.3; IR (thin film, cm-1) 3433, 3032, 2921, 2854, 1629, 1452, 1384, 1151; HRMS (ESI) m/z
[M+H]+Calcd. for C36H31O5 543.2166, Found 543.2173.
6-(Benzyloxy)-2-(2,4-bis(benzyloxy)-6-methoxyphenyl)-3-methylbenzofuran (3). To a suspension of NaH (60%
dispersion in paraffin oil) (40 mg, 1.0 mmol) in THF (4 mL) was added
a
solution of
3,5-bis(benzyloxy)-2-(6-(benzyloxy)-3-methylbenzo furan-2-yl)phenol 2 (488 mg, 0.9 mmol) in dry THF (1 mL) at 0
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 12
1
2
3
4
5
6
7
8
9
°C with stirring under a nitrogen atmosphere. The mixture was then stirred for 1 h at room temperature and
iodomethane (255 mg, 1.8 mmol) was added dropwise over 10 min. The reaction was stirred at room
temperature overnight; the reaction mixture was quenched by the addition of a saturated aqueous solution of
ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, evaporated to dryness and purified by a flash column chromatography
on silica gel (ethyl acetate/petroleum ether = 1:20, Rf = 0.3) to give the product 3 (473 mg) as a yellow oil with a
1
yield of 85%. H NMR (600 MHz, CDCl3) δ 7.49 – 7.29 (m, 11H), 7.25 – 7.18 (m, 5H), 7.09 (d, J = 2.2 Hz, 1H), 6.94
(dd, J = 8.5, 2.2 Hz, 1H), 6.30 (dd, J = 12.4, 2.2 Hz, 2H), 5.12 (s, 2H), 5.06 (s, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 2.07 (s,
3H); 13C NMR (150 MHz, DMSO-d6) δ 161.6, 160.4, 159.4, 156.7, 155.6, 145.2, 137.4, 137.1, 136.7, 128.8, 128.7,
128.5, 128.0, 127.8, 127.7, 127.6, 126.9, 124.4, 119.3, 114.4, 111.4, 102.7, 97.4, 93.6, 92.4, 70.8, 70.7, 70.4, 56.1,
9.0; IR (thin film, cm-1) 3428, 2923, 2855, 1630, 1384, 1101; HRMS (ESI) m/z [M+H]+ Calcd. for C37H33O5 557.2323,
Found 557.2332.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(6-Hydroxy-3-methylbenzofuran-2-yl)-5-methoxybenzene-1,3-diol (4). To
a solution of 6-(benzyloxy)-
2-(2,4-bis(benzyloxy)-6-methoxyphenyl)-3-methyl-benzofuran 3 (390 mg, 0.7 mmol) in methanol (10 mL) was
added 10% Pd/C (40 mg). The reaction vessel was then evacuated and the atmosphere replaced with hydrogen.
After vigorous stirred for 8 h, the reaction mixture was filtered through silica gel and the filtrate was evaporated
to dryness and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf =
0.1) to give the product 4 (170 mg) as a colorless oil with a yield of 85%. 1H NMR (600 MHz, CD3OD) δ 7.25 (d, J =
8.3 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 8.3, 2.1 Hz, 1H), 6.04 (dd, J = 6.7, 2.1 Hz, 2H), 3.68 (s, 3H), 2.00 (s,
3H); 13C NMR (150 MHz, DMSO-d6) δ 160.5, 159.9, 157.8, 155.6, 154.5, 145.1, 123.2, 118.4, 113.4, 110.3, 98.9,
97.0, 95.0, 90.7, 54.6, 7.4; IR (thin film, cm-1) 3450, 2967, 2788, 1695, 1314; HRMS (ESI) m/z [M+H]+ Calcd. for
C16H16O5 287.0914, Found 287.0910.
2-(2-Methoxy-4,6-bis(methoxymethoxy)phenyl)-6-(methoxymethoxy)-3-methylbenzofuran (5). To a suspension
of NaH (60% dispersion in paraffin oil) (40 mg, 1.0 mmol) in dry dimethylformamide (5 mL) was added a solution
of 4-(6-hydroxy-3-methylbenzo furan-2-yl)-5-methoxybenzene-1,3-diol
4 (286 mg, 1.0 mmol) in dry
dimethylformamide (2 mL) at 0 °C with stirring under a nitrogen atmosphere. The mixture was stirred at room
temperature for 1 h and chloromethyl methyl ether (161 mg, 2.0 mmol) was added dropwise at 0 °C over 30 min.
The reaction was stirred at room temperature for 6 h and quenched by the addition of a saturated aqueous
solution of NH4Cl (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, evaporated to dryness. The crude material was purified by a flash
column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.1) to give the product 5 (347
1
mg) as a colorless oil with a yield of 83%. H NMR (600 MHz, DMSO-d6) δ 7.44 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 2.1
Hz, 1H), 6.95 (dd, J = 8.5, 2.1 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 5.26 (s, 2H), 5.22 (s, 2H), 5.11
(s, 2H), 3.70 (s, 3H), 3.43 (s, 3H), 3.40 (s, 3H), 3.25 (s, 3H), 1.98 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 159.8,
159.7, 157.3, 154.5, 154.4, 145.2, 124.4, 119.2, 113.4, 112.3, 102.4, 98.9, 95.6, 94.5, 94.2, 94.0, 93.8, 55.9, 55.8,
55.6, 55.5, 8.4; IR (thin film, cm-1) 3422, 2922, 2853, 1804, 1697, 1492, 1454, 1153, 1025; HRMS (ESI) [M+H]+ m/z
Calcd. for C22H27O8 419.1700, Found 419.1709.
2-(3-Bromo-2-methoxy-4,6-bis(methoxymethoxy)phenyl)-6-(methoxymethoxy)-3-methylbenzofuran (6). To a
solution of 2-(2-methoxy-4,6-bis(methoxymethoxy)phenyl)-6-(methoxymethoxy)-3-methylbenzofuran 5 (418 mg,
1.0 mmol) in DCM (10 mL) was added a solution of N-bromosuccinimide (178 mg, 1.0 mmol) in DCM (5 mL)
dropwise with stirring under a nitrogen atmosphere at 0 °C. The mixture was stirred at room temperature for 1 h.
The reaction mixture was evaporated to dryness. The crude material was purified by a flash column
chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.1) to give the product 6 (174 g) as a
1
colorless oil with a yield of 35%. H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.00
(dd, J = 8.4, 2.1 Hz, 1H), 6.90 (s, 1H), 5.30 (s, 2H), 5.22 (s, 2H), 5.09 (s, 2H), 3.58 (s, 3H), 3.56 (s, 3H), 3.52 (s, 3H),
3.38 (s, 3H), 2.12 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 158.2, 156.9, 156.3, 155.4, 155.3, 144.5, 124.9, 119.5,
115.0, 112.6, 110.2, 101.1, 99.6, 99.5, 95.3, 95.2, 61.5, 56.8, 56.4, 56.1, 8.8; IR (thin film, cm-1) 3422, 2922, 2253,
2126, 1652, 1384, 1051, 1026, 1005; HRMS (ESI) m/z [M+H]+ Calcd. for C22H26O8Br 497.0811, Found 497.0815.
2-(2-Methoxy-4,6-bis(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)phenyl)-6-(methoxymethoxy)-3-methylbenzof
uran (7). To
a solution of 2-(3-bromo-2-methoxy-4,6-bis(methoxymethoxy)phenyl)-6-(methoxymethoxy)-
3-methylbenzofuran 6 (99 mg, 0.2 mmol) in dry dimethylformamide (5 mL) was added cesium carbonate (130
mg, 0.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 0.01 mmol), and
4,4,5,5-tetramethyl-2-(3-methylbut-2-en-1-yl)-1,3,2-dioxaborolane (59 mg, 0.3 mmol) under
a nitrogen
atmosphere. The mixture was stirred at 90 °C for 9 h. The reaction was monitored by TLC till the complete
consumption of the starting material. The reaction mixture was diluted with ethyl acetate (10 mL) and washed
ACS Paragon Plus Environment

Page 7 of 12
The Journal of Organic Chemistry
1
2
3
4
with water (15 mL). The organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to
dryness. The crude material was purified by
a flash column chromatography on silica gel (ethyl
1
acetate/petroleum ether = 1:10, Rf = 0.1) to afford the product 7 (76 mg) as a colorless oil with a yield of 78%. H
NMR (600 MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.4, 2.1 Hz, 1H), 6.61 (s, 1H),
5.25 (s, 2H), 5.24 – 5.22 (m, 1H), 5.21 (s, 2H), 4.64 (s, 2H), 3.75 (s, 3H), 3.51 (s, 6H), 3.40 (d, J = 6.7 Hz, 2H), 3.16 (s,
3H), 2.09 (s, 3H), 1.78 (s, 3H), 1.68 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 158.1, 157.9, 156.3, 155.4, 155.1, 146.1,
131.1, 125.2, 123.6, 119.3, 117.0, 114.5, 112.4, 107.3, 99.8, 99.7, 95.4, 94.8, 94.5, 57.3, 56.21, 56.17, 56.1, 25.9,
23.3, 18.0, 8.8; IR (thin film, cm-1) 3425, 2921, 2827, 1589, 1469, 1381, 1152, 1105; HRMS (ESI) [M+H]+ m/z Calcd.
for C27H35O8 487.2326, Found 487.2335.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Glycybenzofuran (8). To a solution of 2-(2-methoxy-4,6-bis(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)
phenyl)-6-(methoxymethoxy)-3-methylbenzofuran 7 (29 mg, 0.06 mmol) in methanol (5 mL) was added CSA (3
mg, 0.012 mmol) and the resulting mixture was stirred at room temperature for 72 h. The reaction was
monitored by TLC till the complete consumption of the starting material. The reaction mixture was quenched by
the addition of a saturated aqueous solution of Na2CO3 (10 mL) and was extracted with ethyl acetate (10 mL).
The organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude
material was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf =
0.2) to afford the product 8 (16 mg) as a colorless oil with a yield of 75%. 1H NMR (600 MHz, CD3OD) δ 7.30 (d, J =
8.4 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 8.3, 2.1 Hz, 1H), 6.24 (s, 1H), 5.24 – 5.19 (m, 1H), 3.36 (s, 3H),
3.26 (d, J = 6.9 Hz, 2H), 2.06 (s, 3H), 1.75 (s, 3H), 1.67 (d, J = 0.9 Hz, 3H); 13C NMR (150 MHz, CD3OD) δ 160.4,
159.0, 157.0, 156.6, 156.1, 146.7, 130.9, 125.4, 124.4, 120.0, 114.9, 114.5, 112.0, 104.5, 99.4, 98.5, 61.3, 26.0,
23.5, 17.9, 8.8; IR (thin film, cm-1) 3423, 2922, 2854, 1703, 1608, 1443, 1347, 1122; HRMS (ESI) [M+H]+ m/z Calcd.
for C21H23O5 355.1540, Found 355.1542.
7-(Benzyloxy)-6-(6-(benzyloxy)-3-methylbenzofuran-2-yl)-5-methoxy-2,2-dimethylchromane (10). To a solution
of 2-(2-methoxy-4,6-bis(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)phenyl)-6-(methoxymethoxy)-3-methylbenz
ofuran 8 (71 mg, 0.2 mmol) in methanol (5 mL) was added CSA (23 mg, 0.1 mmol) and the resulting mixture was
stirred at 50 °C for 12 h. The reaction was monitored by TLC till the complete consumption of the starting
material. The reaction mixture was quenched by the addition of a saturated aqueous solution of Na2CO3 (10 mL)
and extracted with ethyl acetate (10 mL). The organic layers were washed with brine, dried over anhydrous
Na2SO4 and evaporated to dryness to give the crude compound 9. The crude compound 9 was dissolved in dry
dimethylformamide (2 mL) and added to a suspension of NaH (60% dispersion in paraffin oil) (20 mg, 0.5 mmol)
in dry dimethylformamide (5 mL) at 0 °C with stirring under a nitrogen atmosphere. The mixture was stirred at
room temperature for 30 min and benzyl bromide (86 mg, 0.5 mmol) was added dropwise at 0 °C over 10 min.
The reaction was stirred at room temperature for 3 h. The reaction mixture was quenched by the addition of a
saturated aqueous solution of NH4Cl (5 mL) and extracted with ethyl acetate (10 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was
purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.2) to afford
1
the product 10 (81 mg) as a colorless oil with a yield of 76%. H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 7.4 Hz, 2H),
7.40 (t, J = 8.4 Hz, 3H), 7.34 (t, J = 7.4 Hz, 1H), 7.22-7.26 (m, 5H), 7.12 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.5, 2.1 Hz,
1H), 6.30 (s, 1H), 5.13 (s, 2H), 5.00 (s, 2H), 3.48 (s, 3H), 2.72 (t, J = 6.7 Hz, 2H), 2.11 (s, 3H), 1.80 (t, J = 6.7 Hz, 2H),
1.36 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 159.0, 157.3, 156.8, 156.5, 155.5, 145.6, 137.3, 137.2, 128.7, 128.4,
128.1, 127.7, 127.6, 126.9, 124.4, 119.3, 114.3, 111.4, 107.5, 105.3, 97.7, 97.3, 74.9, 70.7, 70.4, 60.5, 32.5, 17.2,
9.1; IR (thin film, cm-1) 3422, 2972, 2922, 2853, 1753, 1601, 1453, 1384, 1118; HRMS (ESI) m/z [M+H]+ Calcd. for
C35H35O5535.2479, Found 535.2476.
Glycyuralin E (12). The mixture of 7-(benzyloxy)-6-(6-(benzyloxy)-3-methylbenzofuran-2-yl)-5-methoxy-2,2-di
methylchromane 10 (53 mg, 0.1 mmol) and selenium dioxide (11 mg, 0.1 mmol) in dry 1,4-dioxane (3 mL) was
refluxed for 48 h. The resulting black precipitate was filtered off and the crude product was evaporated to
dryness. To the solution of the crude material in methanol (3 mL) was added 20% Pd/C (10 mg). The reaction
vessel was then evacuated and the atmosphere replaced with hydrogen. After vigorous stirring for 8 h, the
reaction mixture was filtered through silica gel and the filtrate was evaporated to dryness. The crude product was
purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf = 0.1) to afford
the product 12 (20 mg) as a colorless oil with a yield of 54%. 1H NMR (600 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.37 (s,
1H), 7.50 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.4, 2.1 Hz, 1H), 6.10 (s, 1H), 4.75 (t, J = 5.4 Hz,
1H), 4.39 (d, J = 5.4 Hz, 2H), 3.41 (s, 3H), 2.58 (t, J = 6.7 Hz, 2H), 1.73 (t, J = 6.7 Hz, 2H), 1.28 (s, 6H); 13C NMR (150
MHz, DMSO-d6) δ 158.4, 155.9, 155.7, 155.2, 154.9, 144.9, 121.0, 120.5, 118.0, 111.1, 105.3, 103.1, 99.0, 97.2,
74.3, 60.0, 54.8, 31.8, 26.5, 18.6, 16.6; IR (thin film, cm-1) 3423, 2922, 2852, 1630, 1458, 1384, 1269, 1110; HRMS
(ESI) m/z [M+H]+ Calcd. for C21H23O6 371.1489, Found 371.1490.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 12
1
2
3
4
5
6
7
8
9
6-(Benzyloxy)-3-((3-methoxyphenoxy)methyl)benzofuran (14). To a solution of (6-(benzyloxy)benzofuran-3-yl)
methanol 1a (2.0 g, 8 mmol), 3-methoxyphenol 13 (1.2 g, 9.6 mmol) and triphenylphosphine (3.2 g, 12 mmol) in
dry THF was added diisopropyl azodiformate (2.4 g, 12 mmol) dropwise at 0 °C under a nitrogen atmosphere over
15 min. The reaction was stirred at room temperature for 4 h. The crude mixture was evaporated to dryness and
purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:20, Rf = 0.4) to afford
the product 14 (1.5 g) as a yellow oil with a yield of 54%. 1H NMR (600 MHz, CDCl3) δ 7.61 (s, 1H), 7.53 (d, J = 8.5
Hz, 1H), 7.47 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.35 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 8.2 Hz, 1H), 7.11 (d, J =
2.2 Hz, 1H), 7.00 (dd, J = 8.0, 2.2 Hz, 1H), 6.63 (dd, J = 8.0, 2.1 Hz, 1H), 6.58 (t, J = 2.1 Hz, 1H), 6.56 (dd, J = 8.2, 2.2
Hz, 1H), 5.15 (d, J = 0.6 Hz, 2H), 5.12 (s, 2H), 3.80 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.0, 160.0, 157.5, 156.6,
142.4, 136.9, 130.1, 128.8, 128.2, 127.6, 120.5, 120.4, 116.8, 112.8, 106.9, 106.8, 101.5, 97.5, 70.7, 61.4, 55.4; IR
(thin film, cm-1) 3501, 2923, 1626, 1592, 1491, 1266, 1154, 1039; HRMS (ESI) m/z [M+H]+ Calcd. for C23H21O4
361.1434, Found 361.1439.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(6-(Benzyloxy)-3-methylbenzofuran-2-yl)-5-methoxyphenol (15). To a solution of 6-(benzyloxy)-3-((3,5-bis(ben
zyloxy)phenoxy)methyl)benzofuran 14 (1.0 g, 2.8 mmol) in DCM (10 mL) was added silica gel (2.0 g) and the DCM
was removed in vacuo. The mixture was heated at 140 °C for 4 h. The crude mixture was purified by a flash
column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.2) to afford the product 15
(655 mg) as a yellow oil with a yield of 65%. 1H NMR (600 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.41 (dd, J = 7.9,
5.5 Hz, 3H), 7.35 (dd, J = 7.8, 4.8 Hz, 2H), 7.09 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.94 (s, 1H), 6.61 (d,
J = 2.4 Hz, 1H), 6.59 (dd, J = 8.5, 2.4 Hz, 1H), 5.13 (s, 2H), 3.84 (s, 3H), 2.33 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
161.5, 157.3, 155.5, 154.3, 148.3, 137.0, 129.9, 128.8, 128.2, 127.6, 124.2, 119.6, 112.6, 111.9, 109.7, 107.3,
102.0, 97.2, 70.8, 55.5, 9.3; IR (thin film, cm-1) 3486, 2923, 2865, 1626, 1593, 1491, 1336, 1254, 1155; HRMS (ESI)
m/z [M+H]+ Calcd. for C23H21O4 361.1434, Found 361.1432.
9-(Benzyloxy)-3-methoxy-6H-benzofuro[3,2-c]chromen-6-one (16). The mixture of 2-(6-(benzyloxy)-3-methyl
benzofuran-2-yl)-5-methoxyphenol 15 (505 mg, 1.4 mmol) and selenium dioxide (155 mg, 1.4 mmol) in dry
1,4-dioxane (5 mL) was refluxed for 48 h. The resulting black precipitate was filtered off and the crude product
was evaporated to dryness. The crude mixture was purified by a flash column chromatography on silica gel (ethyl
acetate/petroleum ether = 1:5, Rf = 0.3) to afford the product 16 (375 mg) as a white solid with a yield of 72%.
Mp 222.4–223.2 °C; 1H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 7.6 Hz,
2H), 7.42 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.12 (dd, J = 8.5, 2.2 Hz, 1H), 6.96-6.98
(m, 2H), 5.16 (s, 2H), 3.90 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 162.7, 160.3, 158.6, 158.4, 156.5, 155.3, 136.6,
128.8, 128.3, 127.7, 122.6, 121.8, 117.0, 114.1, 113.2, 106.2, 103.6, 101.5, 98.1, 70.8, 56.0; IR (thin film, cm-1)
3426, 2921, 2851, 1737, 1625, 1494, 1273, 1257, 1078; HRMS (ESI) m/z [M+H]+ Calcd. for C23H17O5 373.1071
Found 373.1070.
Coumestrol (17). To a solution of 9-(benzyloxy)-3-methoxy-6H-benzofuro[3,2-c]chromen-6-one 16 (101 mg,
0.27 mmol) in dry DCM (5 mL) was added tribromoborane (150 mg, 0.6 mmol) dropwise at −78 °C over 10 min
under a nitrogen atmosphere. The reaction was stirred at room temperature for 12 h and quenched with
methanol at −78 °C. The crude mixture was diluted with ethyl acetate and washed with water and brine, dried
over anhydrous Na2SO4 and evaporated to dryness. The crude material was purified by a flash column
chromatography on silica gel (methanol/DCM = 1:20, Rf = 0.2) to afford the product 17 (58 mg) as a white solid
1
with a yield of 80%. Mp 386.0–387.5 °C; H NMR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.05 (s, 1H), 7.86 (d, J =
8.5 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 6.95 (dd, J = 8.5, 1.9 Hz, 1H), 6.93 (dd, J = 8.5, 2.1 Hz,
1H), 6.91 (d, J = 2.1 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 161.7, 160.0, 158.1, 157.5, 156.4, 155.1, 123.2,
121.1, 115.1, 114.5, 114.2, 104.7, 103.5, 102.5, 99.2; IR (thin film, cm-1) 3420, 2921, 2852, 1629, 1454, 1384,
1261, 1108; HRMS (ESI) m/z [M+H]+ Calcd. for C15H9O5 269.0444, Found 269.0446.
7,2',4'-Trihydroxy-3-benzofurancarboxylic acid (18). Coumestrol 17 (48 mg, 0.18 mmol) was added to an
aqueous solution of 5% NaOH (5 mL) and the reaction was refluxed for 3 h. After cooling, cation exchange resin
(001×7) was added to the solution with stirring at room temperature until the pH of the solution was below 4.
The solution was extracted with ethyl acetate. The combined organic layers were washed with brine and dried
over anhydrous Na2SO4, evaporated to dryness and purified by a flash column chromatography on silica gel
(methanol/ DCM = 1:2, Rf = 0.1) to afford the product 18 (39 mg) as a white solid with a yield of 75%. Mp 218.1–
219.6 °C; 1H NMR (600 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.44 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H),
6.81 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 8.5, 2.0 Hz, 1H), 6.32 (dd, J = 8.5, 2.4 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H);13C NMR
(150 MHz, DMSO-d6) δ 170.4, 159.8, 159.7, 154.9, 154.1, 153.2, 131.2, 123.0, 121.6, 114.6, 112.6, 111.7, 106.7,
106.0, 96.6; IR (thin film, cm-1) 3423, 2924, 2853, 1761, 1600, 1464, 1384, 1258, 1211; HRMS (ESI) m/z [M-H]-
Calcd. for C15H9O6 285.0405, Found 285.0401.
ACS Paragon Plus Environment

Page 9 of 12
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4'-O-Methylcoumestrol (19). To a solution of 9-(benzyloxy)-3-methoxy-6H-benzofuro[3,2-c]chromen-6-one 16
(197 mg, 0.53 mmol) in dry DCM (5 mL) was added tribromoborane (150 mg, 0.6 mmol) dropwise at −78 °C over
10 min under a nitrogen atmosphere. The reaction was stirred for 3 h and quenched with methanol at −78 °C.
The crude mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous
Na2SO4, and evaporated to dryness. The crude material was purified by a flash column chromatography on silica
gel (methanol/DCM = 1:20, Rf = 0.2) to afford the product 19 (120 mg) as a white solid with a yield of 80%. Mp
276.7–278.2 °C; 1H NMR (600 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.20
(d, J = 2.4 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.7, 2.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.1 Hz, 1H), 3.90 (s, 3H);
13C NMR (150 MHz, DMSO-d6) δ 162.3, 159.1, 157.5, 157.2, 156.1, 154.6, 122.5, 120.8, 114.5, 114.2, 113.1, 105.4,
102.8, 101.6, 98.7, 56.1; IR (thin film, cm-1) 3426, 2921, 2851, 1737, 1625, 1494, 1273, 1257; HRMS (ESI) m/z
[M+H]+ Calcd. for C16H11O5 283.0601, Found 283.0603.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-((tert-Butyldimethylsilyl)oxy)-3-methoxy-6H-benzofuro[3,2-c]chromen-6-one (20). To
a
solution of
4'-O-methylcoumestrol 19 (100 mg, 0.35 mmol) in anhydrous dimethylformamide (5 mL) was added
tert-butyldimethylsilyl chloride (60 mg, 0.4 mmol) and imidazole (27 mg, 0.4 mmol) at 0 °C under a nitrogen
atmosphere. The reaction was stirred at room temperature for 1 h. The crude mixture was diluted with water
and extracted with diethyl ether, and the combined organic layers were washed with water and brine, dried over
anhydrous Na2SO4, evaporated to dryness, purified by a flash column chromatography on silica gel (ethyl
acetate/petroleum ether = 1:20, Rf = 0.3) to afford the product 20 (133 mg) as a pale solid with a yield of 95%.
Mp 198.0–199.0 °C; 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz, 1H), 7.84-7.85 (m, 1H), 7.10 (d, J = 2.0 Hz, 1H),
6.94-6.97 (m, 3H), 3.90 (s, 3H), 1.02 (s, 9H), 0.25 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 162.6, 160.2, 158.5, 156.2,
155.2, 155.0, 122.5, 121.4, 118.4, 117.3, 113.0, 106.1, 103.50, 103.48, 101.4, 55.8, 25.7, 18.3, 4.4; IR (thin film,
cm-1) 3455, 2923, 2862, 1751, 1732, 1344, 923, 885; HRMS (ESI) m/z [M+H]+ Calcd. for C22H25O5Si 397.1393,
Found 397.1388.
Lespedezol A1 (21). To
a solution of 9-((tert-butyldimethylsilyl)oxy)-3-methoxy-6H-benzofuro[3,2-c]
chromen-6-one 20 (95 mg, 0.24 mmol) in dry THF (2 mL) was added borane-methyl sulfide complex (2 mol/L
solution in THF, 1.8 mL, 3.5 mmol) dropwise at 0 °C under a nitrogen atmosphere over 10 min. The reaction was
stirred at room temperature for 16 h and quenched with methanol, extracted with ethyl acetate, washed with
water and brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude mixture was dissolved in
THF (5 mL) and tetrabutylammonium fluoride (105 mg, 0.4 mmol) was added at 0 °C under a nitrogen
atmosphere over 10 min. The reaction was stirred at room temperature for 1 h and quenched with water,
extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, evaporated to dryness and
purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf = 0.2) to afford
1
the product 21 (46 mg) as a pale solid with a yield of 49%. Mp 136.2–138.0 °C; H NMR (600 MHz, CDCl3) δ 7.39
(d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 6.7 Hz, 1H), 6.54 (dd, J = 8.4, 2.4 Hz,
1H), 6.51 (s, 1H), 5.56 (s, 2H), 5.00 (s, 1H), 3.81 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.0, 156.3, 155.2, 153.4,
147.5, 121.2, 119.8, 118.7, 112.1, 109.9, 107.3, 105.8, 102.6, 99.1, 65.7, 55.6; IR (thin film, cm-1) 3375, 2922,
2851, 1704, 1632, 1382, 1261, 1093; HRMS (ESI) m/z [M+H]+ Calcd. for C16H13O4 269.0808, Found 269.0810.
6-(Benzyloxy)-3-((3-(benzyloxy)phenoxy)methyl)benzofuran (23). To a solution of (6-(benzyloxy)benzofuran-3-
yl)methanol 1a (2.0 g, 8 mmol), 3-(benzyloxy)phenol 22 (1.9 g, 9.6 mmol) and triphenylphosphine (3.1 g, 12
mmol) in dry THF was added diisopropyl azodiformate (2.4 g, 12 mmol) dropwise at 0 °C under a nitrogen
atmosphere over 15 min. The reaction was stirred at room temperature for 4 h. The crude mixture was
evaporated to dryness and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum
1
ether = 1:50, Rf = 0.2) to afford the product 23 (2.1 g) as a colorless oil with a yield of 61%. H NMR (600 MHz,
CDCl3) δ 7.59 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.39 (q, J = 6.9 Hz,
4H), 7.34 (dd, J = 6.5, 2.9 Hz, 2H), 7.21 (t, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 15.6, 7.8
Hz, 3H), 5.14 (s, 2H), 5.12 (s, 2H), 5.04 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 160.0, 159.8, 157.4, 156.5, 142.3,
136.9, 136.8, 130.0, 128.6, 128.6, 128.0,128.0, 127.5, 127.5, 120.4, 120.2, 116.6, 112.7, 107.6, 107.3, 102.2, 97.4,
70.6, 70.0, 61.3; IR (thin film, cm-1) 3423, 2922, 2851, 1726, 1601, 1588, 1491, 1454, 1386, 1146; HRMS (ESI) m/z
[M+H]+ Calcd. for C29H25O4 437.1747, Found 437.1746.
5-(Benzyloxy)-2-(6-(benzyloxy)-3-methylbenzofuran-2-yl)phenol (24). To a solution of 6-(benzyloxy)-3-((3-
(benzyloxy)phenoxy)methyl)benzofuran 23 (960 mg, 2.2 mmol) in DCM (10 mL) was added silica gel (2.0 g). The
DCM was removed in vacuo. The mixture was heated at 140 °C for 4 h. The crude mixture was purified by a flash
column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.2) to afford the product 24
1
(509 mg) as a colorless oil with a yield of 53%. H NMR (600 MHz, CDCl3) δ 7.47 (t, J = 8.3 Hz, 4H), 7.40-7.43 (m,
5H), 7.34-7.37 (m, 3H), 7.09 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.96 (s, 1H), 6.69 (d, J = 2.5 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 12
1
2
3
4
5
6.66 (dd, J = 8.5, 2.5 Hz, 1H), 5.14 (s, 2H), 5.10 (s, 2H), 2.34 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.6, 157.3,
155.5, 154.3, 148.3, 136.9, 136.8, 129.9, 128.8, 128.22, 128.18, 127.7, 126.6 , 119.6, 112.6, 112.0, 110.0, 108.0,
103.0, 97.2, 70.8, 70.2, 9.3; IR (thin film, cm-1) 3488, 2921, 2863, 1623, 1489, 1249, 1155; HRMS (ESI) m/z [M+H]+
Calcd. for C29H25O4 437.1747, Found 437.1750.
6
7
8
9
6-(Benzyloxy)-2-(4-(benzyloxy)-2-methoxyphenyl)-3-methylbenzofuran (25). To a suspension of NaH (60%
dispersion in paraffin oil) (48 mg, 1.2 mmol) in THF (4 mL) was added solution of
5-(benzyloxy)-2-(6-(benzyloxy)-3-methylbenzofuran-2-yl)phenol 24 (480 mg, 1.1 mmol) in dry THF (1 mL) at 0 °C
with stirring under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h and
iodomethane (312 mg, 2.2 mmol) was added dropwise over 10 min. The reaction was stirred at room
temperature overnight. The reaction mixture was quenched by the addition of a saturated aqueous solution of
NH4Cl (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4 and evaporated to dryness. The crude material was purified by a flash column
chromatography on silica gel (ethyl acetate/petroleum ether = 1:20, Rf = 0.2) to give the product 25 (372 mg) as a
colorless oil with a yield of 75%. 1H NMR (600 MHz, CDCl3) δ 7.47 – 7.27 (m, 12H), 7.07 (d, J = 2.0 Hz, 1H), 6.94
(dd, J = 8.5, 2.1 Hz, 1H), 6.67 – 6.61 (m, 2H), 5.09 (s, 4H), 3.79 (s, 3H), 2.17 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
160.7, 158.5, 156.8, 155.2, 148.5, 137.2, 136.8, 132.0, 128.8, 128.7, 128.2, 128.0, 127.7, 127.6, 124.7, 119.4,
113.4, 112.5, 111.8, 105.6, 99.9, 97.2, 70.7, 70.3, 55.8, 9.3; IR (thin film, cm-1) 3524, 2923, 2853, 1627, 1384,
1111; HRMS (ESI) m/z [M-H]- Calcd. for C30H25O4 449.1759, Found 449.1751.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-(Benzyloxy)-2-(4-(benzyloxy)-2-methoxyphenyl)benzofuran-3-carbaldehyde (26). A mixture of 6-(benzyloxy)-
2-(4-(benzyloxy)-2-methoxyphenyl)-3-methylbenzofuran 25 (302 mg, 0.67 mmol) and selenium dioxide (74 mg,
0.67 mmol) in dry 1,4-dioxane (5 mL) was refluxed for 48 h. The resulting black precipitate was filtered off and
the crude material was evaporated to dryness and purified by a flash column chromatography on silica gel (ethyl
acetate/petroleum ether = 1:5, Rf = 0.4) to afford the product 26 (212 mg) as a colorless oil with a yield of 68%. 1H
NMR (600 MHz, CDCl3) δ 10.06 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.41 (m, 10H), 7.12 (s, 1H),
7.07 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.69 (s, 1H), 5.15 (s, 2H), 5.13 (s, 2H), 3.83 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 187.9, 162.5, 162.4, 158.7, 157.7, 155.4, 136.8, 136.3, 132.9, 128.9, 128.7, 128.4, 128.2, 127.7,
127.6, 122.7, 118.9, 117.8, 113.8, 111.0, 106.2, 100.0, 97.1, 70.6, 70.5, 55.8; IR (thin film, cm-1) 3032, 2925, 2854,
1734, 1664, 1611, 1583, 1494, 1380, 1260, 1141, 1064; HRMS (ESI) m/z [M+H]+ Calcd. for C30H25O5 465.1697,
Found 465.1702.
Puerariafuran (27). To
a
solution of 6-(benzyloxy)-2-(4-(benzyloxy)-2-methoxyphenyl)benzofuran-
3-carbaldehyde 26 (186 mg, 0.4 mmol) in dry DCM (5 mL) was added tribromoborane (200 mg, 0.8 mmol)
dropwise at −78 °C under a nitrogen atmosphere over 10 min. The reaction was stirred for 3 h and quenched
with methanol at −78 °C. The crude mixture was diluted with ethyl acetate and washed with water and brine,
dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was purified by a flash column
chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf = 0.1) to afford the product 27 (96 mg) as a
1
yellow solid with a yield of 85%. Mp 293.6–295.1 °C; H NMR (600 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.83 (d, J = 8.4
Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 1.7 Hz, 1H), 6.85 (dd, J = 8.4, 1.7 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 6.56
(dd, J = 8.4, 1.6 Hz, 1H), 3.77 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 187.2, 162.3, 161.7, 158.6, 156.3, 154.9,
132.7, 121.6, 116.6, 113.6, 108.0, 107.8, 99.7, 97.7, 55.6; IR (thin film, cm-1) 3405, 2924, 2852, 1621, 1443, 1383,
1132; HRMS (ESI) m/z [M+H]+ Calcd. for C16H13O5 285.0757, Found 285.0761.
ASSOCIATED CONTENT
1
The Supporting Information is available free of charge on the ACS Publications website. H and 13C NMR spectra
for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
Email: yongxiang.liu@syphu.edu.cn; mscheng@syphu.edu.cn.
ORCID
Yongxiang Liu: 0000-0003-0364-0137
Notes
ACS Paragon Plus Environment

Page 11 of 12
The Journal of Organic Chemistry
1
2
3
The authors declare no competing financial interest.
4
5
ACKNOWLEDGMENTS
6
7
8
We were grateful to the Natural Science Foundation of Liaoning Province of China for financial support (grant
20170540855). We acknowledged the program for innovative research team of the Ministry of Education and the
program for Liaoning innovative research team in university.
9
REFERENCES
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1 (a) Chang, H. M.; Cheng, K. P.; Tai, F. C.; Chow, H. F.; Chui, K. Y. J. Org. Chem. 1990, 55, 3537-3543. (b)
Wine-Show, S.; Ian-Lih, T.; Teng, C. M.; Chen, I. S. Phytochemistry 1994, 36, 213-215. (c) Melo, P. A.;
Nascimento, M. C. D.; Mors, W. B.; Suarez-Kurtz, G. Toxicon 1994, 32, 595-603. (d) Chen, Y.; Wei, X. Y.; Xie, H.
H.; Deng, H. Z. J. Nat. Prod. 2008, 71, 929-932. (e) Mori-Hongo, M.; Takimoto, H.; Katagiri, T.; Kimura, M.; Ikeda,
Y.; Miyase, T. J. Nat. Prod. 2009, 72, 194-203.
2 Khanam, H.; Shamsuzzaman. Eur. J. Med. Chem. 2015, 97, 483-504. (b) Naik, R.; Harmalkar, D. S.; Xu, X.; Jang,
K.; Lee, K. Eur. J. Med. Chem. 2015, 90, 379-393.
3 (a) Bickoff, E. M.; Booth, A. N.; Lyman, R. L.; Livingston, A. L.; Thompson, C. R.; Kohler, G. O. J. Agr. Food Chem.
1958, 6, 536-539. (b) Bickoff, E. M.; Livingston, A. L.; Witt, S. C.; Lundin, R. E.; Spencer, R. R. J. Agr. Food Chem.
1965, 13, 597-599. (c) Miyase, T.; Sano, M.; Nakai, H.; Muraoka, M.; Nakazawa, M.; Suzuki, M.; Yoshino, K.;
Nishihara, Y.; Tanai, J. Phytochemistry 1999, 52, 303-310. (d) Kim, N. H.; Kim, Y. S.; Lee, Y. M.; Jang, D. S.; Kim, J.
S. Biol. Pharm. Bull. 2010, 33, 1605-1609. (e) Li, S. P.; Li, W.; Wang, Y. H.; Asada, Y.; Koike, K. Bioorg. Med. Chem.
Lett. 2010, 20, 5398-5401. (f) Yuk, H. J.; Lee, J. H.; Curtis-Long, M. J.; Lee, J. W.; Kim, Y. S.; Ryu, H. W.; Park, C. G.;
Jeong, T. S.; Park, K. H. Food Chem. 2011, 126, 1057-1063. (g) Ji, S.; Li, Z.; Song, W.; Wang, Y.; Liang, W.; Li, K.;
Tang, S.; Wang, Q.; Qiao, X.; Zhou, D.; Yu, S.; Ye, M. J. Nat. Prod. 2016, 79, 281-292.
4 (a) Mann, I.; Widdowson, D.; Clough, J. Tetrahedron 1991, 47, 7991-8000. (b) Yao, T.; Yue, D.; Larock, R. J. Org.
Chem. 2005, 70, 9985-9989. (c) Furstner, A.; Heilmann, E. K.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
4760-4763. (d) Kaur, N.; Xia, Y.; Jin, Y.; Dat, N. T.; Gajulapati, K.; Choi, Y.; Hong, Y.; Lee, J. J.; Lee, K. Chem.
Commun. 2009, 40, 1879-1881. (e) Pahari, P.; Rohr, J. J. Org. Chem. 2009, 74, 2750-2754. (f) Tricotet, T.;
Fleming, P.; Cotter, J.; Hogan, A. M.; Strohmann, C.; Gessner, V.; O’Shea, D. J. Am. Chem. Soc. 2009, 131,
3142-3143. (g) Tang, L.; Pang, Y.; Yan, Q.; Shi, L.; Huang, J.; Du, Y.; Zhao, K. J. Org. Chem. 2011, 76, 2744-2752.
(h) Kapdi, A. R.; Karbelkar, A.; Naik, M.; Pednekar, S.; Fischer, C.; Schulzke, C.; Tromp, M. RSC Adv. 2013, 3,
20905-20912. (i) Kshirsagar, U. A.; Parnes, R.; Goldshtein, H.; Ofir, R.; Zarivach, R.; Pappo, D. Chem. Eur. J. 2013,
19, 13575-13583.
5 (a) Wang, E. C.; Wein, Y. S.; Kuo, Y. H. Tetrahedron Lett. 2006, 47, 9195-9197. (b) Zhang, J.; Qiu, J.; Xiao, C.; Yu,
L.; Yang, F.; Tang, J. Eur. J. Org. Chem. 2016, 2016, 3380-3385.
6 (a) Verma, P.; Singh, S. Synthesis 1988, 01, 168-170. (b) Pearson, J.; Porter, Q. Aust. J. Chem. 1991, 44, 907-917.
(c) Zhu, J. B.; Wang, P.; Liao, S.; Tang, Y. Org. Lett. 2013, 15, 3054-3057. (d) Ghosh, R.; Stridfeldt, E.; Olofsson, B.
Chem. Eur. J. 2014, 20, 8888-8892. (e) Shibuta, T.; Sato, S.; Shibuya, M.; Kanoh, N.; Taniguchi, T.; Monde, K.;
Iwabuchi, Y. Heterocycles 2014, 89, 631-639. (f) Zhou, Z.; Liu, G.; Chen, Y.; Lu, X. Org. Lett. 2015, 17, 5874-5877.
7 (a) Mitsunobu, O. Synthesis 1981, 1, 1-28. (b) Zürcher, M.; Hof, F.; Barandun, L.; Schütz, A.; Schweizer, W. B.;
Meyer, S.; Bur, D.; Diederich, F. Eur. J. Org. Chem. 2009, 2009, 1707-1719. (c) Yin, B.; Cai, C.; Zeng, G.; Zhang, R.;
Li, X.; Jiang, H. Org. Lett. 2012, 14, 1098-1101. (d) Fowler, K.; Ellis, J.; Morrow, G. Synth. Commun. 2013, 43,
1676-1682.
8 (a) Hatayama, K.; Yokomori, S.; Kawashima, Y.; Saziki, R.; Kyogoku, K. Chem. Pharm. Bull. 1985, 33, 1327-1333.
(b) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127-164. (c) Dodge, J.; Jones, S. Rec. Res. Dev. Org. Chem.
1997, 1, 273-283. (d) Viton, F.; Landreau, C. Eur. J. Org. Chem. 2008, 2008, 6069-6078. (e) Kishali, N.; Polat, M.;
Altundas, R.; Kara, Y. Helv. Chim. Acta. 2008, 91, 67-72. (f) Yuan, H.; Bi, K. J.; Li, B.; Yue, R. C.; Ye, J. Org. Lett.
2013, 15, 4742-4745.
9 Nayak, M.; Jung, Y.; Kim, I. Org. Biomol. Chem. 2016, 14, 8074-8087.
10 Sun, H.; Li, Y.; Zhang, X.; Lei, Y.; Ding, W.; Zhao, X.; Wang, H.; Song, X.; Yao, Q. W.; Zhang, Y.; Ma, Y. Bioorg.
Med. Chem. Lett. 2015, 25, 4567-4571.
11 Miralles, N.; Alam, R.; Szabó, K.; Fernández, E. Angew. Chem., Int. Ed. 2016, 55, 4303-4307.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table of Contents
ACS Paragon Plus Environment