Chemoselective acid-catalyzed [4 + 2]-cycloaddition reactions of: Ortho -quinone methides and styrenes/stilbenes/cinnamates

Article abstract of DOI:10.1039/d0ob01312a

ortho-Quinone methides (o-QMs) generated from the corresponding benzyl acetate precursors chemoselectively underwent the formal [4 + 2]-cycloadditions with the olefin of styrene, stilbene, or cinnamate derivatives by using different transition metal salts or Br?nsted acids. Such selectivity was obtained when these olefins either separately acted as the dienophiles or were simultaneously present on the same dienophiles. Complete selectivity was also achieved between the stilbene olefin and acetylene to furnish the key chroman intermediate for the subsequent ring-closing metathesis (RCM), affording the corresponding tetracyclic 5H-dihydronaphtho[1,2-c]chromene. This journal is

Full text of DOI:10.1039/d0ob01312a

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21 December 2017
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DOI: 10.1039/D0OB01312A
Journal Name
ARTICLE
Chemoselective Acid-Catalyzed [4+2]-Cycloaddition Reactions of
ortho-Quinone Methides and Styrenes/Stilbenes/Cinnamates
Received 00th January 20xx,
Accepted 00th January 20xx
Kornkamon Akkarasereenon,a Kassrin Tangdenpaisal,b Somsak Ruchirawat a,b,c and Poonsakdi
Ploypradith*a,b, c
DOI: 10.1039/x0xx00000x
ortho-Quinone methides (o-QMs) generated from the corresponding benzyl acetate precursors chemoselectively
underwent the formal [4+2]-cycloadditions with the olefin of styrene, stilbene, or cinnamate derivatives by using different
transition metal salts or Brønsted acids. Such selectivity was obtained when these olefins either separately acted as the
dienophiles or were simultaneously present on the same dienophiles. Complete selectivity was also achieved between the
stilbene olefin and acetylene to furnish the key chroman intermediate for the subsequent ring-closing metathesis (RCM),
affording the corresponding tetracyclic 5H-dihydronaphtho[1,2-c]chromene.
H
O
O
O
Introduction
O
OH
MeO2C
HO
HO
ortho-Quinone methides (o-QMs) have served as important
intermediates in organic synthesis, bioorganic chemistry, and
biosynthesis of natural products.1,2 Their utilization during the
total synthesis of complex natural products has been well
documented.3 Among their chemical reactivity, the formal
[4+2]-cycloaddition reactions with electron-rich dienophiles,
where o-QMs were regarded as the electron-deficient dienes,
could furnish the corresponding chromans arising from the
inverse electron-demand Diels-Alder-type process. As shown
in Fig. 1, various chroman-containing natural products, namely
rubicordifolin (1),4 rubioncolin (2),5 berkelic acid (3),6
cytosporolide (4),7 psidial A (5),8 and psiguadial C (6)9 were
readily prepared via total synthesis employing this chemistry.
As shown in Scheme 1, over the past few years, our
research group has actively investigated the reactions of o-
QMs generated from the benzyl acetate precursor 7 with (E)-
styrene 8a, (E)-chalcone 8b, or (E)-cinnamate 8c under the
mediation/catalysis of p-toluenesulfonic acid immobilized on
silica (PTS-Si) and some transition metal salts such as PtCl4 to
generate the corresponding 3/4-substituted 2-arylchroman 9a,
9b, or 9c, respectively, in good to excellent yields (up to 99%)
and trans stereocontrol at C2–C3 (>99:1) as well as
predominantly cis stereochemistry at C2–C4 (up to >99:1).10
We now envisioned that such formal [4+2]-cycloaddition
reactions of o-QMs could be extended to stilbenes 10 to
provide the corresponding 2,3-diaryl-4-substiutted chromans
11. More importantly, we anticipated that, by using different
transition metals/Brønsted acids, these olefin-containing
O
H
O
H
O
O
H
MeO2C
OH
HO
OH
MeO2C
rubicordifolin (1)
rubioncolin B (2)
C7H15
C5H11
H
O
OMe
O
H
H
O
CO2Me
O
H
H
O
HO
HO
Et
HO
O
CO2H
CO2H
OH
cytosporolide A (4)
berkelic acid (3)
OH
Ph
O
OH
Ph
H
Me
OHC
HO
OHC
HO
O
H
O
H
CHO
CHO
H
psidial A (5)
psiguadial C (6)
Fig. 1 Representative chroman-containing natural products 1-6 accessible via the
formal [4+2]-cycloaddition reactions of o-QMs.
dienophiles may undergo chemoselective [4+2]-cycloaddition
reactions in a controlled and desirable manner. Herein, we
wish to report catalyst- and substrate-controlled
chemoselectivity when these formal [4+2]-cycloaddition
reactions were performed competitively on the mixture of
these dienophiles to afford 9a, 9c, or 11. Alternatively, these
reactions would be performed on single molecules of
dienophiles simultaneously containing two different types of
these olefins to afford the cycloadducts 12. On the basis of
chemoselectivity between alkyne and stilbene, a key chroman
intermediate bearing two intact TMS acetylene groups would
be prepared which could afford the corresponding tetracyclic
5H-dihydronaphtho[1,2-c]chromene 13 upon subsequent steps
including the Ru(II)-catalyzed ring-closing metathesis (RCM).
a. Program in Chemical Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal
Academy, 906 Kamphaeng Phet 6 Road, Bangkok, Thailand 10210.
b. Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54
Kamphaeng Phet 6 Road, Bangkok, Thailand 10210.
c. Centre of Excellence on Environmental Health and Toxicology, Commission on
Higher Education (CHE), Ministry of Education, Thailand 10400.
†Electronic Supplementary Information (ESI) available: Detailed experimental for
the preparation of compounds 28-30 and copies of 1H and 13C NMR spectra. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
Table 1 Optimization for the [4+2]-cycloaddition reactions of 15 and 16a
up to >99:1(H:H)
View Article Online
R
R
H
R'
DOI: 10.1039/D0OB01312A
R'
Br
Br
H
E
Ar
8a-c
OAc
OMOM
Br
Ph
Br
Ph
OAc Ph
16
PTS-Si or PtCl4
up to 99%
MeO
MeO
O
Ar
catalyst/mediator
H
MeO
OMOM
MeO
O
Ph
previous work
H
7
8a & 9a, R' = H
15
17
8b & 9b, R' = COAr'
8c & 9c, R' = CO2Et
Ar2
Yieldb (%)
0
MLn
this work
Entry
1c
Mediator (mol%)
PTS-Si (110)
Ar1
10
R
2
PtCl4 (10)
0
H
H
H
Br
Ar2
Ar1
Br
3
4
5
6
7
8
CuTC (10) or CuI (10)
CuBr2 (10) or Cu(OTf)2 (10)
FeCl2 (10-100)
FeCl3 (10)
InCl3 (10)
MgCl2 (10)
0
0
< 20
31
40
0
H
MeO
O
MeO
O
H
OMe
11
13
R1
H
Br
Y
12
X
9
Mg(ClO4)2 (10)
Ag(TFA)2 (5)
37
0
31
47
0
44
58
48
MeO
O
H
10
11
12d
13
14
15e
16f
O
Bi(OTf)3 (10)
Sc(OTf)3 (5-10)
Yb(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (5)
Scheme 1 [4+2]-Cycloaddition reactions of o-QMs and olefins under acid catalysis.
Results and Discussion
In(OTf)3 (1)
Because the reaction conditions for the [4+2]-cycloaddition
reactions of o-QMs and stilbenes have not been optimized,
benzyl acetate 15 and the commercially available (E)-stilbene
16 were used as models while various transition metal salts or
Brønsted acids were employed as catalyst/mediator. As
summarized in Table 1, neither the use of stoichiometric
aUnless noted otherwise, the reactions were carried out in CH2Cl2 as solvent and
performed at 0 °C to room temperature until the benzyl acetate was completely
consumed as indicated by tlc. bIsolated yields. cToluene was employed as solvent.
dUse of 20 mol% gave the product in lower yield (33%). eThe reaction was
f
performed at 0–15 °C for 1 h. The reaction was carried out at 0–15 °C for 3 h;
performing the reaction at
0 °C to room temperature for 18 h led to
decomposition of 15 without any detectable amount of the product 17.
10c
amount of PTS-Si10a,b nor catalytic amount of PtCl4 gave the
corresponding chroman 17 (entries 1–2); similar results were
also found when different salts of Cu(I) and Cu(II) were used as
catalyst (entries 3–4). In contrast, catalytic amount of the
chloride salts of Fe(II) and Fe(III) gave 17 in low yields (up to
31%; entries 5–6)11 while slightly better yield of 40% was
obtained from InCl3 (entry 7).12 Interestingly, while MgCl2 did
not give any product, Mg(ClO4)213 could furnish 17 in 37% yield
(entries 8–9). Silver trifluoroacetate did not provide the
product (entry 10) but various transition metal triflates except
Yb(OTf)3 furnished 17 in moderate to good yields (up to 58%;
entries 11–15).14 Apparently, the reaction conditions (amount
of catalyst, temperature, and reaction time) contributed
towards the yields when In(OTf)3 was employed. Therefore,
the optimized condition for the reaction between 15 and 16
was the use of 5-10 mol% of In(OTf)3 at 0–15 °C for 1 h.15
Previously, we reported that the dienophiles bearing an
electron-donating methoxy group at the 4-position of the
aromatic ring of styrenes or cinnamates gave the cycloadducts
in better yields than those with proton or electron-
withdrawing group at the same position.10 Thus, in order to
assess the difference in the reactivity of styrenes, stilbenes,
and cinnamates in the [4+2]-cycloaddition reactions, we
decided to employ styrene 18, stilbene 19, and cinnamate 20
as the dienophiles while using benzyl acetate 15 and 21 as the
o-QM precursors. Three transition metals/Brønsted acids,
namely PTS-Si, PtCl4, and In(OTf)3, were utilized as the catalyst/
mediator to furnish the corresponding cycloadducts 22-27 in
moderate to excellent yields (up to 99%). The results were
summarized in Fig. 2.
For the electron-rich styrene 18, catalytic amount of both
PtCl4 and In(OTf)3 led to their complete decomposition,
presumably the polymerization, prior to catalyzing the
formation of the corresponding o-QM from 15. Therefore, for
electron-rich styrenes, only PTS-Si was effective, affording the
product 22 in excellent yield (99%). The results were
somewhat different when the reactions were evaluated using
o-QM generated from the benzyl acetate 21. While PTS-Si was
still the most effective mediator and furnished the cycloadduct
25 in 57% yield (4:1 mixture of the C4 epimers favoring C2-C4
in a cis relationship), both PtCl4 and In(OTf)3 could also provide
25 in 19% (4:1 mixture) and 40% (1.5:1 mixture) yields,
respectively. In case of the stilbene 19, both PTS-Si and
In(OTf)3 could provide the product 23 in excellent yields of 94%
and 90%, respectively, while PtCl4 in moderate 43% yield.
Similar results were also obtained when stilbene 19 reacted
with the o-QM from the benzyl acetate 21. The reactions
afforded the corresponding cycloadduct 26 in moderate to
good yields of 84%, 37%, and 75% from PTS-Si, PtCl4, and
In(OTf)3, respectively, with excellent diastereocontrol at C2-C4
of >10:1 favoring the cis relationship in all cases. When the
cinnamate 20 was employed, all three catalysts/mediators
could furnish the chromans 24 and 27 from the corresponding
benzyl acetates 15 and 21, respectively, in moderate to good
yields (58–80%). In case of 15, PtCl4 gave the best yield of 76%
while PTS-Si gave the best yield of 80% for 21. Chroman 27 was
obtained with moderate diastereoselectivity between C2-C4 of
3:1 favoring the cis relationship in all cases.
2 | J. Name., 2012, 00, 1-3
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Table 2 Competitive [4+2]-cycloaddition reactionsa
R
R
H
H
View Article Online
catalyst/mediator
conditions
Br
Br
X
DOI: 10.1039/D0OB01312A
OAc
OMOM
R
R
H
catalyst/mediator
conditions
X
Br
Br
X
MeO
Ar
MeO
O
Ar
OAc
OMOM
15, R = H
Ar = (4-OMe)C6H4
18, X = H; 19, X = Ph; 20, X = CO2Et
X
21, R = (4-OMe)C6H4
MeO
MeO
O
Ar
Ar
H
H
15, R = H
22, R = X = H
Br
Ph
Ar
Br
21, R = (4-OMe)C6H4
Ar = (4-OMe)C6H4
18, X = H
23, R = H; X = Ph
24, R = H; X = CO2Et
25, R = (4-OMe)C6H4; X = H
26, R = (4-OMe)C6H4; X = Ph
MeO
23 (15 + 19)
O
MeO
O
Ar
19, X = Ph
H
20, X = CO2Et
27, R = (4-OMe)C6H4; X = CO2Et
22 (15 + 18)
Ar = (4-OMe)C6H4
PTS-Si: 94%
PtCl4: 43%
Ar = (4-OMe)C6H4
PTS-Si: 99%
PtCl4: 0%
Entry Benzyl
Dienophile
Mediator
(mol%)
Yieldb (%)
Acetate
15
In(OTf)3: 90%
In(OTf)3: 0%
1
18+19
18+19
18+20
18+20
19+20
19+20
19+20
18+19+20
18+19+20
18+19
18+19
18+20
18+20
19+20
19+20
19+20
PTS-Si (110)
In(OTf)3 (10)
PTS-Si (110)
In(OTf)3 (10)
PTS-Si (110)
PtCl4 (10)
In(OTf)3 (10)
PTS-Si (110)
In(OTf)3 (10)
PTS-Si (110)
In(OTf)3 (10)
PTS-Si (110)
PtCl4 (10)
22 (20) : 23 (25)
22 (0) : 23 (80)
22 (26) : 24 (0)
22 (0) : 24 (26)
23 (62) : 24 (0)
23 (54) : 24 (0)
23 (61) : 24 (0)
22 (23) : 23 (8) : 24 (0)
22 (0) : 23 (54) : 24 (0)
25 (68) : 26 (0)
25 (28) : 26 (0)
25 (60) : 27 (0)
25 (57) : 27 (31)
26 (51) : 27 (29)d
26 (58) : 27 (0)
Ar
H
2
15
Br
Br
CO2Et
Ar
4
3
15
MeO
25 (21 + 18)
O
Ar
4
15
MeO
24 (15 + 20)
O
H
H
5c
6c
7c
8
15
15
15
15
Ar = (4-OMe)C6H4
PTS-Si: 61%
PtCl4: 76%
Ar = (4-OMe)C6H4
PTS-Si: 57% (4:1)a
PtCl4: 19% (4:1)a
In(OTf)3: 58%
In(OTf)3: 40% (1.5:1)a
Ar
H
Ar
H
9
15
Br
Ph
Ar
Br
CO2Et
Ar
10
11
12
13
14
15
16
17
18
19
21
21
21
21
21
21
21
21
4
4
MeO
26 (21 + 19)
Ar = (4-OMe)C6H4
O
MeO
O
H
H
27 (21 + 20)
Ar = (4-OMe)C6H4
PTS-Si: 80% (3:1)a
PtCl4: 69% (3:1)a
In(OTf)3: 74% (3:1)a
PTS-Si (110)
PtCl4 (10)
In(OTf)3 (10)
PTS-Si (110)
PtCl4 (10)
PTS-Si: 84% (>10:1)a
PtCl4: 37% (>10:1)a
In(OTf)3: 75% (>10:1)a
26 (89) : 27 (0)
18+19+20
18+19+20
18+19+20
25 (60) : 26 (0) : 27 (0)
25 (25) : 26 (28) : 27 (0)
25 (50) : 26 (0) : 27 (0)
Fig. 2 [4+2]-Cycloaddition reactions of 15 and 21 with dienophiles 18–20 using PTS-Si,
21
21
a
PtCl4, or In(OTf)3 as catalyst/mediator. H:H at C4.
In(OTf)3 (10)
aUnless noted otherwise, all reactions were performed using CH2Cl2 as solvent until the
benzyl acetate 15 or 21 was completely consumed as indicated by tlc; 2 equivalents of
18, 19, and/or 20 were added. bIsolated yield. c20 was recovered virtually quantitatively
(>97%) while approximately 27% yield of 19 was recovered. dObtained as a 2:1 mixture
of two C4 epimers favoring cis.
Having established the reaction conditions for each
dienophile, we turned our attention to assess the outcome of
the reactions when two or all three dienophiles were
simultaneously present in the reactions (Table 2). This would
shed some light on the relative kinetics of each dienophile
under the catalysis/mediation of PTS-Si, PtCl4, or In(OTf)3.
Some generalizations could be made based on the results
shown in Table 2. In most cases (except entries 4, 13, and 14),
complete orthogonality for the [4+2]-cycloaddition reactions,
which excluded the cinnamate 20 as a dienophile, were
observed; the corresponding cycloadducts 24 and 27 were not
obtained and 20 could be recovered virtually quantitatively. In
addition, o-QM from the benzyl acetate 21 generally favored
the [4+2]-cycloaddition reactions with styrene 18 to furnish
the chroman 25 (entries 10–13 and 17–19). When comparing
benzyl acetates 15 and 21 as the o-QM precursors, the
presence of a PMB group in 21 apparently affected and
facilitated the [4+2]-cycloaddition with each reacting
dienophile to furnish the corresponding cycloadducts in better
yields (entry 1 vs 10, entry 3 vs 12, entry 7 vs 16, and entry 8 vs
17). Because PtCl4 caused extensive decomposition of the
styrene 18 when reacting with o-QM from 15 as shown in
Figure 2, we decided not to employ PtCl4 as a catalyst when
styrene 18 was used as a dienophile (entries 1–4 and 8–9). In
general, when PTS-Si was employed, low yields (20-26%) of the
chroman 22 were obtained from the reactions of 15 with the
styrene 18 in the presence of either the stilbene 19 and/or
cinnamate 20 (entries 1, 3, and 8). In these cases, both
chromans 22 and 23 were obtained virtually as 1:1 mixture.
Interestingly, when catalytic amount of In(OTf)3 was used, in
the presence of both 18 and 19, the o-QM from 15 selectively
reacted with 19 to furnish 23 in 80% yield (entry 2). In
addition, in the presence of 18 and 20, only chroman 24 from
the reaction between the o-QM and the cinnamate 20 was
obtained in low yield of 26% (entry 4). In both cases, as
monitored by tlc, substantial decomposition of 18 was evident
and preceded the cycloaddition reactions. In cases where both
stilbene 19 and cinnamate 20 were simultaneously present,
using PTS-Si, PtCl4, or In(OTf)3 only furnished the chroman 23
in moderate 54–62% yields (entries 5–7). Similar results were
also obtained when the benzyl acetate 21 was employed as
substrate (entries 14–16); In(OTf)3 gave the best yield of
chroman 26 (89%) while PtCl4 in moderate 58% yield. When
the three dienophiles were present, the selectivity depended
on the o-QM substrate (15 vs 21) and the catalyst/mediator.
With PTS-Si as a mediator, both 15 and 21 preferably gave the
cycloadduct 22 and 25 arising from the reactions with the
styrene 18 in 23% and 60% yields, respectively (entries 8 and
17). However, when In(OTf)3 was employed, different types of
the chroman product were obtained from 15 and 21.
Compound 15 reacted selectively with stilbene 19 to furnish 23
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/D0OB01312A
R
catalyst/mediator
conditions
Br
X
Y
OAc
OMOM
products 31a-31f and 31a'-31f'
+
MeO
O
15, R = H
28, X = H; Y = Ph
21, R = (4-OMe)C6H4
29, X = H; Y = CO2Et
30, X = Ph; Y = CO2Et
15 + 28
A: 31a (44%) +
31a' (9%)
B: 31a (7%) +
31a' (8%)
C: 31a (23%) +
31a' (4%)
H
Br
Br
Ph
EtO2C
EtO2C
Br
Ph
MeO
O
MeO
O
O
O
O
O
OMe
H
H
O
O
O
O
O
O
31a
31b
31c
31a'
31b'
31c'
15 + 29
Br
Br
Br
A: 31b (59%)
B: 31b (52%)
C: 31b (37%)
31b' (0%) in all cases
CO2Et
MeO
MeO
O
O
OMe
H
H
H
H
H
15 + 30
Br
Ph
Br
Ph
Br
A: 31c (61%)
B: 31c (71%)
C: 31c (66%)
31c' (0%) in all cases
CO2Et
MeO
MeO
O
OMe
H
H
H
H:H = 3.7:1 (A)
6.7:1 (B)
PMP
PMP
PMP
21 + 28
Br
Br
Ph
Br
A: 31d (49%)
B: 31d (22%)
C: 31d (42%)
31d' (0%) in all cases
4.4:1 (C)
Ph
MeO
O
H
MeO
O
H
O
OMe
H
H
O
O
31d
31d'
H:H = 3.6:1 (A)
6.3:1 (B)
PMP
PMP
PMP
21 + 29
Br
Br
EtO2C
Br
A: 31e (53%)
B: 31e (50%)
C: 31e (66%)
31e' (0%) in all cases
5.5:1 (C)
CO2Et
MeO
MeO
O
H
O
H
O
OMe
H
O
O
31e
31e'
H:H = 1:0 (A)
1:0 (B)
PMP
H
PMP
H
PMP
O
H
H
21 + 30
Br
Ph
Br
Ph
EtO2C
Br
A: 31f (35%)
B: 31f (48%)
C: 31f (47%)
31f' (trace for B)
1:0 (C)
CO2Et
MeO
MeO
O
H
O
H
OMe
O
O
31f
31f'
PMP
H:H = 4.0:1 (B)
H
H
2.6:1 (C)
21, CH2Cl2
rt, 2 h
Br
Br
EtO2C
Br
CO2Et
B: 40%
MeO
O
MeO
O
O
OMe
C: 46%
O
O
31b
32
Scheme 2 Chemoselective [4+2]-cycloaddition reactions of benzyl acetates 15 and 21 with dienophiles 28–30 containing two different olefins. A = PTS-Si; B = PtCl4; C = In(OTf)3.
4 | J. Name., 2012, 00, 1-3
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ARTICLE
in 54% yield (entry 9) while 21 reacted with styrene 18 to PtCl4 and In(OTf)3 could affect such cycloaddition reaction,
provide 25 in 50% yield (entry 19). furnishing the desired product 32 in moderate yields of 40%
With the above results, we then investigated the reactions and 46% and C2-C4 diastereoselectivity of 4:1 and 2.6:1,
between the benzyl acetate 15 or 21 with compounds 28–3016 respectively.
each of which contains two different olefin functionalities
Interestingly, as shown in Scheme 3, alkyne could be
acting as dienophiles on the same molecule: 28 containing tolerated during the catalysis of In(OTf)3 between the o-QM
styrene and stilbene moieties, 29 containing styrene and precursor 33 bearing a TMS acetylene and stilbene 16 or 19.
cinnamate moieties, and 30 containing stilbene and cinnamate The corresponding chromans 34 and 35 were obtained in 79%
moieties. We anticipated that cycloaddition reactions should and 98% yields, each as a 10:1 and a 3:1 mixture of C4-
proceed with high selectivity among these olefins acting as epimers, respectively. The presence of an alkyne on the
dienophiles. The results were depicted in Scheme 2. In most dienophile was also evaluated; the stilbene-alkyne 36 bearing
cases, excellent selectivity among different olefins was another TMS acetylene moiety ortho to the stilbene was
observed; the only exceptions were the cases where o-QM prepared for this purpose via sequential Heck and Sonogashira
from 15 reacted with 28, yielding both 31a and 31a’ arising cross-coupling reactions of 2-bromoiodobenzene 37 in 95%
from the reactions of o-QM on both styrene and stilbene
TMS
TMS
moieties regardless of the catalyst/mediator. Compound 31a
was obtained as the major product when using PTS-Si (44%
yield) or In(OTf)3 (23% yield). In each case, 31a’ was obtained
only in low yields (4–9%). PtCl4, on the other hand, gave both
31a (7% yield) and 31a’ (8% yield) without any selectivity.
Ar
Ph
Ha:Hb
H
16, Ar = Ph
Br
Br
Ph
H
19, Ar = (4-OMe)C6H4
OAc
OMOM
In(OTf)3 (5 mol%)
CH2Cl2, 0-15 °C, 3 h
MeO
MeO
O
Ar
33
34, Ar = Ph (79%; 10:1)
35, Ar = (4-OMe)C6H4
(98%; 3:1)
Apparently, there were
a number of inseparable and
uncharacterizable products from the decomposition of 28
under the reaction conditions or from different side reactions,
leading to low mass balance, especially for PtCl4. To our
delight, in other cases, whether o-QM from 15 or 21 was
employed as substrate to react with 28–30, the corresponding
products 31b–31f were obtained from the mono-cycloaddition
reaction on one of the two dienophiles with only trace
amount, if any, of the undesired 31b’–31f’. Similar to the
results obtained above (Table 2), virtually no reactions took
place on the cinnamate moiety of compounds 29 and 30 in all
cases regardless of the catalysts/mediators.17 Interestingly,
when compound 28 reacted with benzyl acetate 21, excellent
selectivity was also obtained on the styrene even when PtCl4
was employed; however, the yields of the product 31d
remained moderate (less than 49%). In case of compound 29,
the resulting cycloadducts 31b and 31e were furnished equally
effectively from both 15 (37–59% yields) and 21 (50–66%
yields) with PTS-Si and In(OTf)3 as the best catalyst/mediator,
respectively. For compound 30, consistently higher yields (61–
71%) of 31c from the benzyl acetate 15 were obtained when
compared with those (35–48%) of 31f from the benzyl acetate
21; the range of yields for both o-QM precursors appeared to
be independent of the catalyst/mediator. Regarding the C2-C4
stereoselectivity for the cycloadducts 31d–f, 31d and 31e were
obtained as mixtures of C4-epimers favoring 2,4-cis
relationship in the ratios of 3.6:1–6.7:1; PtCl4 consistently gave
the best C2-C4 diastereoselectivity among the mediators.
Surprisingly, 31f was obtained as a single diastereomer
regardless of the mediators. We further demonstrated that the
sequential [4+2]-cycloaddition reaction could be realized by
employing 31b, the cycloadduct from the benzyl acetate 15
and compound 29, as a starting material for the subsequent
[4+2]-cycloaddition reaction using the benzyl acetate 21. Both
Ar
Ar, Pd(OAc)2
Na2CO3, DMF, 95%
TMS
PdCl2(PPh3)2, DMF, 91%
1)
2)
I
conditions
, CuI, Et3N
Br
TMS
37
36, Ar = (4-OMe)C6H4
TMS
TMS
TMS
TMS
H
H
Br
Br
H
O
H
+
MeO
Ar
MeO
O
H
Ar
H
38
38'
Conditions:
1) In(OTf)3 5 mol%, 0-10 °C, 0.75 h
38 (55%) : 38' (28%)
2) In(OTf)3 1 mol%, 0-20 °C, 4 h
38 (47%) : 38' (20%)
3) Sc(OTf)3 5 mol%, 0-5 °C, 0.5 h
38 (52%) : 38' (23%)
38 TBAF, 90%
H
Br
4) InCl3 5 mol%, 0-20 °C, 2 h
38 (40%) : 38' (23%)
H
MeO
O
Ar
H
39
Lindlar's catalyst
H2, 77%
H
4
Br
3
HG-II
H
O
2
(20 mol%)
PhMe
MeO
Ar
H
H
Br
H
Br
MeO
H
3
4
Ar
MeO
O
Ar
H
H
4
2
O
+
40
13 (53%)
H
H
Br
Br
MeO
H
3
Ar
2
MeO
O
Ar
O
H
13' (not formed)
41 (28%)
Scheme 3 Synthesis of the tetracyclic 5H-dihydronaphtho[1,2-c]chromene 13.
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and 91% yields, respectively.18 In(OTf)3-catalyzed [4+2]- group manipulations of the chroman 38 containViniegw Atrwticole OTnMlinSe
DOI: 10.1039/D0OB01312A
cycloaddition required some additional optimization; 5 mol% acetylene groups then led to the synthesis of tetracyclic 5H-
of In(OTf)3 furnished the chroman 38 in 55% yield with the C2- dihydronaphtho[1,2-c]chromene in 20% overall yield in 4 steps
C4 in the cis relationship along with 38’, its C4-epimer, in 28% starting from the [4+2]-cycloaddition reaction.
yield. Subsequent treatment of 38 with tetrabutylammonium
fluoride (TBAF) smoothly cleaved both TMS groups and gave
39 in 90% yield which was then subjected to hydrogenation
Experimental section
using Lindlar’s catalyst. The diene 40 was obtained in 77%
yield; Hoveyda-Grubbs II (HG-II)-catalyzed ring closing
metathesis (RCM) of 40 proceeded rather sluggishly, requiring
heating at 70 °C and 80 °C for 24 h each. The desired
tetracyclic 5H-dihydronaphtho[1,2-c]chromene 13 was finally
obtained in 53% yield along with the aromatized 5H-
naphtho[1,2-c]chromene 41 in 28% yield. Other reaction
conditions (other catalysts, higher temperatures with shorter
reaction times, or lower temperatures with longer reaction
times) gave no improvement of yields or selectivity between
13 and 41.
It should be noted that 38’ could not undergo such
reaction sequence smoothly, especially the final RCM to
furnish 13’. Apparently, the difference in stereochemistry at C4
of 38’ affected its reactivity which led to undesired side
reactions and low yields of the products from TBAF desilylation
as well as Lindlar’s hydrogenation. More importantly, the
resulting diene was unreactive during the RCM and could be
recovered virtually quantitatively under various conditions.
This could be accounted for by considering and comparing the
conformations of 13, which was obtained from 38, and 13’,
which would otherwise be the product from 38’. The geometry
required for the ring fusion between the cyclohexene and the
aromatic ring of the dihydronaphthalene unit would
necessitate the two adjacent bonds on the aromatic ring (blue
and pink for 13 vs red and pink for 13’) to assume coplanarity;
clearly, the conformation in 13 would be more optimal. In part,
this also results from the more favorable pseudoequatorial-
pseudoequatorial ring fusion (blue bonds; H3-H4 in the trans
relationship) in 13 than the pseudoequatorial-pseudoaxial ring
fusion (red bonds; H3-H4 in the cis relationship) in 13’.
General Information
Unless otherwise noted, reactions were run in oven-dried
round-bottomed flasks. Tetrahydrofuran (THF) was distilled
from sodium benzophenone ketyl or purified by the solvent
purification system while dichloromethane (CH2Cl2) was also
purified by the solvent purification system prior to use. All
other compounds were used as received from the suppliers;
PTS-Si (p-TsOH immobilized on silica) employed in these
experiments possessed the surface area of 500 m2/g as
indicated by the supplier. The crude reaction mixtures were
concentrated under reduced pressure by removing organic
solvents on rotary evaporator. Column chromatography was
performed using silica gel 60 (particle size 0.06-0.2 mm; 70-
230 mesh ASTM). Analytical thin-layer chromatography (TLC)
was performed with silica gel 60 F254 aluminum sheets.
Chemical shifts for 1H nuclear magnetic resonance (NMR)
spectra were reported in parts per million (ppm,) downfield
from tetramethylsilane. Splitting patterns are described as
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m),
broad (br), doublet of doublet (dd), doublet of triplet (dt), and
doublet of doublet of doublet (ddd). All 13C NMR data were
obtained with the use of broadband decoupling (13C{1H}) and
reported as proton-decoupled data. Resonances for infrared
(IR) spectra were reported in wavenumbers (cm-1). Low
resolution (LRMS) mass spectra were obtained either using
electron ionization (EI) or time-of-flight (TOF) while high
resolution (HRMS) mass spectra were obtained using time-of-
flight (TOF) via the atmospheric-pressure chemical ionization
(APCI) or electrospray ionization (ESI). Melting points were
uncorrected.
General procedure for the formal [4+2]-cycloaddition reaction
To a stirred solution of benzyl acetate (1.0 equiv) in toluene
(for PTS-Si as mediator) or CH2Cl2 (for other transition metals
as Lewis acids) (15 mL/mmol) was added the corresponding
alkene (2 equiv) at room temperature. The resulting mixture
was stirred at 0 °C for 10 min and then PTS-Si (1.1 equiv) or
transition-metals (10 mol%) was added. The stirring was
continued (for time and temperature as indicated for each
substrate). At that time, in case of PTS-Si, it was filtered off
before the resulting mixture was concentrated under reduced
pressure. In other cases, the reaction mixture was
concentrated under reduced pressure directly to give a crude
product mixture which was further purified by PTLC (10%
EtOAc/hexane) to furnish the desired product.
Conclusions
In summary, we have demonstrated that under different
transition metal salt/Brønsted acid-catalyzed formal [4+2]-
cycloaddition reaction conditions, three classes of structurally
related olefins conjugated with aromatic rings containing
electron-donating methoxy group, namely styrenes, stilbenes,
and cinnamates, could chemoselectively react with ortho-
quinone methides (o-QMs) generated under the same reaction
conditions from the corresponding benzyl acetates to furnish
the corresponding cycloadducts in moderate to excellent
yields. Such chemoselectivity could also be obtained when two
or more possible dienophiles were present simultaneously in
the reaction or two different olefins were present on the same
molecule of the dienophile. In addition, complete
chemoselectivity was also observed between the stilbene
moiety and the TMS acetylene groups present on both o-QM
and the aromatic ring of the stilbene. Subsequent functional
6-Bromo-7-methoxy-2,3-diphenylchroman (17).
Following the General Procedure, benzyl acetate 15 (0.020 g,
0.06 mmol), (E)-1,2-diphenylethene 16 (0.023 g, 0.13 mmol),
and In(OTf)3 (0.002 g, 0.003 mmol) were employed to give 17
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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1
as a white sticky gum (0.014 g, 0.037 mmol, 58%); H NMR major); 13C{1H} NMR (75 MHz, CDCl3):  38.0 (minor), 38.6
View Article Online
(300 MHz, CDCl3):  2.91–3.05 (m, 1H), 3.11–3.29 (m, 2H), 3.83 (minor), 40.1 (major), 41.9 (major), 55.2D(mOIa: 1jo0.r1)0,3595/D.30O(mB0a1j3o12r)A,
(s, 3H), 5.05 (d, J = 9.2 Hz, 1H), 6.54 (s, 1H), 6.97–7.02 (m, 2H), 56.1 (major), 73.2 (minor), 78.3 (major), 100.86 (minor),
7.08–7.23 (m, 8H), 7.28 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3):  100.94 (major), 102.2 (major), 102.3 (minor), 113.82 (minor),
32.2, 45.4, 56.2, 83.0, 101.0, 102.1, 115.6, 126.8, 127.1, 113.84 (minor), 113.9 (major), 114.1 (major), 116.8 (minor),
127.98, 128.03, 128.1, 128.4, 132.8, 139.3, 140.8, 154.9, 155.1; 119.6 (major), 127.4 (minor), 127.5 (major), 129.3 (major),
TOF-HRMS (m/z): [M + H+], calcd for C20H2079BrO2, 395.0641; 129.4 (minor), 132.7 (major), 132.9 (minor), 133.2 (major),
found, 395.0633; calcd for C20H2081BrO2, 397.0623; found, 134.1 (minor), 135.8 (major), 137.7 (minor), 155.0 (major),
397.0621.
6-Bromo-7-methoxy-2-(4-methoxyphenyl)-3-phenylchro-man 158.5 (major), 159.3 (minor), 159.5 (major); TOF-HRMS (m/z):
(23).
[M + H+], calcd for C24H24O479Br, 455.0852; found, 455.2249;
155.3 (minor), 155.5 (minor), 155.7 (major), 158.2 (minor),
Following the General Procedure, benzyl acetate 15 (0.020 g, calcd for C24H24O481Br, 457.0832; found, 457.0857.
0.06 mmol), (E)-1-methoxy-4-styrylbenzene 19 (0.0263 g, 0.12 6-Bromo-7-methoxy-2,4-bis(4-methoxyphenyl)-3-phenyl-
mmol), and PTS-Si (0.0851 g, 0.07 mmol) were employed to chroman (26).
give 23 as a white solid (0.024 g, 0.057 mmol, 94%); Mp Following the General Procedure, benzyl acetate 21 (0.025 g,
1
130−132 °C; H NMR (300 MHz, CDCl3):  2.93–3.02 (m, 1H), 0.06 mmol), (E)-1-methoxy-4-styrylbenzene 19 (0.025 g, 0.12
3.11–3.28 (m, 2H), 3.73 (s, 3H), 3.83 (s, 3H), 5.02 (d, J = 9.4 Hz, mmol), and PTS-Si (0.081 g, 0.066 mmol) were employed to
1H), 6.54 (s, 1H), 6.73 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 6.6 Hz, give 26 as a white solid (0.027 g, 0.050 mmol, 84%) of a >10:1
2H), 7.09 (d, J = 8.7 Hz, 2H), 7.12–7.22 (m, 3H), 7.28 (s, 1H); mixture of C4-epimers; Mp 193.3–195.0 C; 1H NMR (300 MHz,
13C{1H} NMR (75 MHz, CDCl3):  32.6, 45.3, 55.1, 56.2, 82.6, CDCl3):  3.24 (dd, J = 11.1, 10.5 Hz, 1H), 3.69 (s, 3H), 3.71 (s,
100.9, 102.0, 113.5, 115.6, 126.7, 128.0, 128.3, 128.5, 131.4, 3H), 3.82 (s, 3H), 4.33 (d, J = 11.1 Hz, 1H), 5.18 (d, J = 10.5 Hz,
132.7, 141.0, 154.9, 155.0, 159.2; TOF-HRMS (m/z): [M ], 1H), 6.54 (s, 1H), 6.67 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 8.6 Hz,
calcd for C23H21O379Br, 424.0674; found, 424.0666; calcd for 2H), 6.73–6.79 (m, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.92 (s, 1H),
C23H21O381Br, 426.0654; found, 426.0647.
Ethyl-6-bromo-7-methoxy-2-(4-methoxyphenyl)chroman-3-
carboxylate (24).
6.96–7.06 (m, 3H), 7.11 (d, J = 8.6 Hz, 2H); 13C{1H} NMR (75
MHz, CDCl3):  49.0, 54.4, 55.0, 55.1, 56.2, 82.7, 100.8, 102.5,
113.5, 113.7, 120.3, 126.4, 128.1, 128.5, 129.8, 131.1, 133.7,
Following the General Procedure, benzyl acetate 15 (0.050 g, 134.4, 139.4, 155.0, 155.4, 158.1, 159.2; TOF-HRMS (m/z): [M
0.16 mmol), ethyl (E)-3-(4-methoxyphenyl)acrylate 20 (0.065 g, + H+], calcd for C30H28O479Br, 531.1165; found, 531.1159; calcd
0.31 mmol), and PTS-Si (0.213 g, 0.17 mmol) were employed to for C30H28O481Br, 533.1146; found, 533.1136.
1
give 24 as colorless oil (0.040 g, 0.096 mmol, 61%); H NMR Ethyl-6-bromo-7-methoxy-2,4-bis(4-methoxyphenyl)-
(300 MHz, CDCl3):  0.99 (t, J = 7.1 Hz, 3H), 2.92 (dd, J = 15.2, chroman-3-carboxylate (27).
4.7 Hz, 1H), 3.02 (m, 1H), 3.19 (dd, J = 14.8, 10.9 Hz, 1H), 3.81 Following the General Procedure, benzyl acetate 21 (0.025 g,
(s, 5H), 3.95 (qd, J = 7.1, 1.2 Hz, 2H), 5.00 (d, J = 9.1 Hz, 1H), 0.06 mmol), ethyl (E)-3-(4-methoxyphenyl)acrylate 20 (0.025 g,
6.48 (s, 1H), 6.90 (d, J = 8.7 Hz, 2H), 7.26 (s, 1H), 7.32 (d, J = 8.7 0.06 mmol), and PTS-Si (0.081 g, 0.066 mmol) were employed
Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3):  13.9, 28.0, 45.4, 55.3, to give 27 as a white sticky gum (0.026 g, 0.048 mmol, 80%) as
56.2, 60.7, 79.0, 101.0, 102.5, 113.5, 113.9, 128.4, 130.3, a 3:1 mixture of C4-epimers; 1H NMR (300 MHz, CDCl3):  0.72
132.8, 154.5, 155.1, 159.9, 172.2; TOF-HRMS (m/z): [M ], (t, J = 7.1 Hz, 3H, major), 0.91 (t, J = 7.1 Hz, 3H, minor), 3.10
calcd for C20H21O579Br, 420.0572; found, 420.0570; calcd for (dd, J = 11.4, 10.2 Hz, 1H, major), 3.43 (dd, J = 11.0, 5.8 Hz, 1H,
C20H21O581Br, 422.0552; found, 422.0548.
6-Bromo-7-methoxy-2,4-bis(4-methoxyphenyl)chroman (25).
minor), 3.63–3.75 (m, 2H), 3.778 (s, 3H, minor), 3.783 (s, 3H,
minor), 3.795 (s, 3H, major), 3.800 (s, 3H, major), 3.81 (s, 3H,
Following the General Procedure, benzyl acetate 21 (0.025 g, major), 3.83 (s, 3H, minor), 4.44 (d, J = 5.8 Hz, 1H, minor), 4.45
0.06 mmol), 1-methoxy-4-vinylbenzene 18 (10 L, 0.12 mmol), (d, J = 11.4 Hz, 1H, major), 5.10 (d, J = 10.2 Hz, 1H, major), 5.19
and PTS-Si (0.081 g, 0.066 mmol) were employed to give 25 a (d, J = 11.0 Hz, 1H, minor), 6.50 (s, 1H, major), 6.53 (s, 1H,
yellow oil (0.016 g, 0.034 mmol, 57%) as a 4:1 mixture of C4- minor), 6.82 (d, J = 8.7 Hz, 2H, minor), 6.84 (d, J = 8.7 Hz, 2H,
1
epimers; H NMR (300 MHz, CDCl3):  2.13 (ddd, J = 2.1, 3.2, major), 6.86 (d, J = 8.7 Hz, 2H, minor), 6.895 (d, J = 8.7 Hz, 2H,
13.8 Hz, 1H, minor), 2.19 (ddd, J = 11.2, 11.8, 13.7 Hz, 1H, major), 6.899 (s, 1H, major), 6.99 (d, J = 8.7 Hz, 2H, minor),
major), 2.31 (ddd, J = 2.1, 6.0, 13.7 Hz, 1H, major), 2.38 (ddd, J 7.08 (d, J = 8.7 Hz, 2H, major), 7.14 (d, J = 8.7 Hz, 2H, minor),
= 5.5, 10.6, 13.8 Hz, 1H, minor), 3.77 (s, 3H, minor), 3.78 (s, 3H, 7.31 (d, J = 8.7 Hz, 2H, minor), 7.36 (d, J = 8.7 Hz, 2H, major);
minor), 3.79 (s, 3H, major), 3.80 (s, 3H, major), 3.81 (s, 3H, 13C{1H} NMR (75 MHz, CDCl3):  13.7, 42.7 (minor), 45.5
major), 3.85 (s, 3H, minor), 4.10 (dd, J = 3.2, 5.5 Hz, 1H, minor), (major), 50.4 (minor), 54.8 (major), 55.18 (major), 55.21
4.18 (dd, J = 6.0, 11.8 Hz, 1H, major), 4.94 (dd, J = 2.1, 10.6 Hz, (minor), 55.3 (major), 56.2 (major), 60.27 (minor), 60.35
1H, minor), 5.11 (dd, J = 2.1, 11.2 Hz, 1H, major), 6.50 (s, 1H, (major), 73.7 (minor), 79.8 (major), 100.5 (major), 100.7
major), 6.56 (s, 1H, minor), 6.84 (d, J = 8.6 Hz, 2H, minor), (minor), 102.9 (major), 113.6 (minor), 113.7 (minor), 113.9
6.858 (d, J = 8.7 Hz, 2H, major), 6.864 (d, J = 8.6 Hz, 2H, minor), (major), 114.1 (major), 116.5 (minor), 118.5 (major), 128.6
6.90 (s, 1H, major), 6.91 (d, J = 8.7 Hz, 2H, major), 7.02 (d, J = (major), 129.1 (minor), 129.7 (major), 129.8 (major), 130.3,
8.6 Hz, 2H, minor), 7.11 (d, J = 8.7 Hz, 2H, major), 7.13 (s, 1H, (minor), 131.0 (minor), 132.9 (major), 133.2 (major), 133.5
minor), 7.23 (d, J = 8.6 Hz, 2H, minor), 7.37 (d, J = 8.7 Hz, 2H, (minor), 133.7 (minor), 154.5 (minor), 154.8 (major), 155.2
This journal is © The Royal Society of Chemistry 20xx
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(major), 155.5 (minor), 158.77 (minor), 158.81 (major), 159.7 128.1, 128.5, 128.6, 132.8, 133.1, 134.4, 135.9, 140.7, 154.8,
View Article Online
(minor), 160.0 (major), 169.9 (minor), 171.3 (major); TOF- 154.9, 155.1, 155.1, 156.6, 157.0; TOFD-HORI:M10S.10(3m9//Dz0):OB[M01312]A,
HRMS (m/z): [M + H+], calcd for C27H2879BrO6, 527.1064; found, calcd for C38H32O579Br2, 726.0616; found, 726.0602 and calcd
527.1057; calcd for C27H2881BrO6, 529.1044; found, 529.1033.
for C38H32O579Br81Br, 728.0598; found, 728.0577; calcd for
C38H32O581Br2, 730.0585; found, 730.0558.
(E)-1-Styryl-4-(4-vinylphenoxy)benzene (28).16
Mp 158−159 °C; 1H NMR (300 MHz, CDCl3):  5.21 (dd, J = 10.9, Ethyl
(E)-3-(4-(4-(6-bromo-7-methoxychroman-2-
0.6 Hz, 1H), 5.68 (dd, J = 17.6, 0.6 Hz, 1H), 6.70 (dd, J = 17.6, yl)phenoxy)phenyl)acrylate (31b).
10.9 Hz, 1H), 6.98–7.02 (m, 4H), 7.06 (d, J = 6.9 Hz, 2H), 7.23– Following the General Procedure, benzyl acetate 15 (0.052 g,
7.29 (m, 1H), 7.33–7.43 (m, 4H), 7.48–7.52 (m, 4H); 13C{1H} 0.16 mmol), compound 29 (0.093 g, 0.31 mmol), and PTS-Si
NMR (75 MHz, CDCl3):  112.9, 118.9, 119.0, 126.4, 127.5, (0.213 g, 0.17 mmol) were employed to give 31b as a white
1
127.6, 127.8, 127.9, 128.7, 132.7, 133.0, 136.0, 137.4, 156.7, foam (0.049 g, 0.09 mmol, 59%); H NMR (300 MHz, CDCl3): 
156.8; TOF-HRMS (m/z): [M + H+], calcd for C22H19O, 299.1430; 1.34 (t, J = 7.1 Hz, 3H), 1.99–2.13 (m, 1H), 2.16–2.24 (m, 1H),
found, 299.1429.
2.69–2.77 (m, 1H), 2.86–2.98 (m, 1H), 3.83 (s, 3H), 4.26 (q, J =
7.1 Hz, 2H), 5.02 (dd, J = 10.1, 2.3 Hz, 1H), 6.35 (d, J = 16.0 Hz,
Ethyl (E)-3-(4-(4-vinylphenoxy)phenyl)acrylate (29).16
1
Mp 58−59 °C; H NMR (300 MHz, CDCl3):  1.34 (t, J = 7.1 Hz, 1H), 6.49 (s, 1H), 6.99 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.6 Hz,
3H), 4.26 (q, J = 7.1 Hz, 2H), 5.23 (dd, J = 10.9, 0.6 Hz, 1H), 5.69 2H), 7.24 (s, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.7 Hz,
(dd, J = 17.6, 0.6 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 6.71 (dd, J = 2H), 7.66 (d, J = 16.0 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3): 
17.7, 11.0 Hz, 1H), 6.99–7.02 (m, 4H), 7.41 (d, J = 8.6 Hz, 2H), 14.3, 24.1, 29.6, 56.2, 60.4, 77.6, 101.1, 102.0, 115.1, 117.0,
7.49 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 16.0 Hz, 1H); 13C{1H} NMR 118.5, 119.6, 127.7, 129.4, 129.7, 133.0, 136.9, 143.7, 154.9,
(75 MHz, CDCl3):  14.3, 60.4, 113.4, 117.0, 118.4, 119.6, 155.0, 155.9, 159.2, 167.0; TOF-HRMS (m/z): [M + H+], calcd
127.7, 129.3, 129.7, 133.7, 135.9, 143.8, 155.8, 159.3, 167.1; for C27H26O579Br, 509.0958; found, 509.0943; calcd for
TOF-HRMS (m/z): [M + H+], calcd for C19H19O3, 295.1329; C27H26O581Br, 511.0938; found, 511.0921.
found, 295.1331.
Ethyl (E)-3-(4-(4-((E)-styryl)phenoxy)phenyl)acrylate (30).16
Ethyl
(E)-3-(4-(4-(6-bromo-7-methoxy-3-phenylchroman-2-
yl)phenoxy)phenyl)acrylate (31c).
Mp 148−149 °C; 1H NMR (300 MHz, CDCl3):  1.34 (t, J = 7.1 Hz, Following the General Procedure, benzyl acetate 15 (0.071 g,
3H), 4.27 (q, J = 7.1 Hz, 2H), 6.35 (d, J = 16.0 Hz, 1H), 6.97–7.09 0.22 mmol), compound 30 (0.163 g, 0.44 mmol), and PtCl4
(m, 6H), 7.24–7.29 (m, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.49–7.53 (7.40 mg, 0.02 mmol) were employed to give 31c as a white
1
(m, 6H), 7.67 (d, J = 16.0 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3): foam (0.092 g, 0.16 mmol, 71%); H NMR (300 MHz, CDCl3): 
 14.3, 60.4, 117.0, 118.5, 119.8, 126.4, 127.6, 127.7, 128.0, 1.33 (t, J = 7.1 Hz, 3H), 2.94–3.04 (m, 1H), 3.14–3.27 (m, 2H),
128.3, 128.7, 129.4, 129.7, 133.4, 137.2, 143.8, 155.7, 159.3, 3.84 (s, 3H), 4.26 (q, J = 7.1 Hz, 2H), 5.04 (d, J = 9.1 Hz, 1H),
167.1; TOF-HRMS (m/z): [M + H+], calcd for C25H23O3, 6.33 (d, J = 16.0 Hz, 1H), 6.55 (s, 1H), 6.87 (d, J = 8.6 Hz, 4H),
371.1642; found, 371.1642.
(E)-6-Bromo-7-methoxy-2-(4-(4-styrylphenoxy)phenyl)-
chroman (31a).
7.00 (d, J = 6.5 Hz, 2H), 7.12–7.24 (m, 5H), 7.29 (s, 1H), 7.45 (d,
J = 8.7 Hz, 2H), 7.64 (d, J = 16.0 Hz, 1H); 13C{1H} NMR (75 MHz,
CDCl3):  14.3, 32.2, 45.7, 56.2, 60.4, 82.5, 100.9, 102.3, 115.5,
Following the General Procedure, benzyl acetate 15 (0.031 g, 117.0, 118.2, 119.4, 126.9, 128.0, 128.5, 128.7, 129.2, 129.6,
0.09 mmol), compound 28 (0.056 g, 0.19 mmol), and PTS-Si 132.8, 135.2, 140.6, 143.7, 154.7, 155.0, 155.6, 159.3, 167.1;
(0.128 g, 0.103 mmol) were employed to give 31a as a white TOF-HRMS (m/z): [M + H+], calcd for C33H30O579Br, 585.1271;
foam (0.021 g, 0.04 mmol, 44%) along with 31a’ as a white found, 585.1275; calcd for C33H30O581Br, 587.1253; found,
foam (0.0033 g, 0.005 mmol, 5%).
587.1253.
31a: 1H NMR (300 MHz, CDCl3):  2.00–2.24 (m, 2H), 2.70–2.78 6-Bromo-7-methoxy-4-(4-methoxybenzyl)-2-(4-(4-((E)-
(m, 1H), 2.87–2.98 (m, 1H), 3.83 (s, 2H), 5.02 (dd, J = 10.1, 2.2 styryl)phenoxy)phenyl)chroman (31d).
Hz, 1H), 6.50 (s, 1H), 7.00 (s, 1H), 7.03–7.05 (m, 5H), 7.23–7.28 Following the General Procedure, benzyl acetate 21 (0.050 g,
(m, 2H), 7.34–7.41 (m, 4H), 7.48–7.52 (m, 4H); 13C{1H} NMR (75 0.12 mmol), compound 28 (0.071 g, 0.24 mmol), and PTS-Si
MHz, CDCl3):  24.2, 29.6, 56.2, 77.7, 101.1, 102.0, 115.1, (0.16 g, 0.13 mmol) were employed to give 31d as a white
118.9, 119.1, 126.4, 127.5, 127.6, 127.8, 127.9, 128.7, 132.7, foam (0.036 g, 0.06 mmol, 49%) of a 3.7:1 mixture of C4-
1
133.1, 136.1, 137.3, 154.9, 155.1, 156.7, 156.9; TOF-HRMS epimers, favoring the cis C2-C4; H NMR (300 MHz, CDCl3): 
(m/z): [M ], calcd for C30H25O379Br, 512.0987; found, 2.15–2.27 (m, 2H, major, minor), 2.34 (dd, J = 5.8, 1.9 Hz, 1H,
512.0977; calcd for C30H25O381Br, 514.0967; found, 514.0950.
major), 2.38 (dd, J = 5.9, 2.0 Hz, 1H, minor), 3.81 (s, 3H, minor),
(31a’): 1H NMR (300 MHz, CDCl3):  1.98 – 2.21 (m, 2H), 2.68 – 3.82 (s, 3H, major), 3.85 (s, 3H, major), 3.88 (s, 3H, minor), 4.14
2.77 (m, 1H), 2.86 –3.04 (m, 2H), 3.16 –3.26 (m, 1H), 3.21 (d, J (dd, J = 5.1, 3.3 Hz, 1H, minor), 4.22 (dd, J = 11.9, 6.0 Hz, 1H,
= 8.5 Hz, 1H), 3.83 (s, 3H), 3.85 (s, 3H), 4.99 (dd, J = 10.1, 2.1 major), 4.99 (dd, J = 10.6, 2.3 Hz, 1H, minor), 5.17 (dd, J = 11.2,
Hz, 1H), 5.04 (d, J = 8.3 Hz, 1H), 6.48 (s, 1H), 6.55 (s, 1H), 6.85 1.6 Hz, 1H, major), 6.53 (s, 1H, major), 6.58 (s, 1H, minor),
(d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 6.9 Hz, 6.85-6.92 (m, 8H, major, minor), 6.97–7.03 (m, 6H, major,
2H), 7.13 (d, J = 8.7 Hz, 4H), 7.17–7.22 (m, 3H), 7.24 (s, 1H), minor), 7.04–7.05 (m, 4H, major, minor), 7.07 (s, 2H, major,
7.29 (s, 1H), 7.34 (d, J = 8.5 Hz, 2H); 13C{1H} NMR (75 MHz, minor), 7.10–7.16 (m, 6H, major, minor), 7.23–7.29 (m, 2H,
CDCl3):  24.2, 29.6, 32.3, 45.7, 56.2, 56.3, 77.7, 82.6, 100.9, major, minor), 7.36 (t, J = 7.5 Hz, 4H, major, minor), 7.43–7.52
101.1, 102.0, 102.2, 115.1, 115.5, 118.7, 118.8, 126.9, 127.5, (m, 10H, major, minor); 13C{1H} NMR (75 MHz, CDCl3):  38.2
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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(minor), 38.7 (minor), 40.3 (major), 41.9 (major), 55.3 (major), Ethyl
56.2 (major), 73.2 (minor), 78.2 (major), 100.9 (minor), 101.0 phenylchroman-2-yl)phenoxy)phenyl)-7-methoxy-4-(4-
(major), 102.4 (major), 102.5 (minor), 113.9 (minor), 114.2 methoxybenzyl)chroman-3-carboxylate (32).
ARTICLE
6-bromo-2-(4-(4-(6-bromo-7-methoxy-3-
View Article Online
DOI: 10.1039/D0OB01312A
(major), 116.8 (minor), 118.4 (minor), 118.9 (minor), 119.0 Following the General Procedure, benzyl acetate 21 (0.021 g,
(minor), 119.0 (major), 119.6 (major), 126.4 (major), 127.5 0.049 mmol), compound 31b (0.050 g, 0.098 mmol), and PtCl4
(minor), 127.7 (major), 127.8 (minor), 127.8 (major), 127.9 (1.7 mg, 0.005 mmol) were employed to give 32 as a white
(minor), 128.2 (minor), 128.7 (major), 128.8 (minor), 129.3 foam (0.0164 g, 0.02 mmol, 40%) of a 4:1 mixture of C4-
1
(major), 129.4 (minor), 130.3 (minor), 132.7 (major), 133.3 epimers, favoring the cis C2-C4; H NMR (300 MHz, CDCl3): 
(major), 134.2 (minor), 135.7 (major), 135.7 (major), 135.8 0.77 (t, J = 7.1 Hz, 3H, major), 0.94 (t, J = 7.1 Hz, 3H, minor),
(minor), 137.3 (major), 137.7 (minor), 155.1 (major), 155.4 1.98–2.13 (m, 2H, major, minor), 2.15–2.23 (m, 2H, major,
(minor), 155.5 (major), 156.7 (major), 156.8 (minor), 157.0 minor), 2.69–2.77 (m, 2H, major, minor), 2.86–2.98 (m, 2H,
(major), 158.2 (minor), 158.5 (major); TOF-HRMS (m/z): [M + major, minor), 3.06–3.15 (m, 2H, major, minor), 3.67–3.76 (m,
H+], calcd for C37H31O479BrNa, 641.1298; found, 641.1290; 4H, major, minor), 3.79 (s, 3H, minor), 3.80 (s, 3H, major), 3.81
calcd for C37H31O481BrNa, 643.1280; found, 643.1284.
Ethyl (E)-3-(4-(4-(6-bromo-7-methoxy-4-(4- 3H, minor), 4.47 (d, J = 11.2 Hz, 1H, major), 4.49 (d, J = 19.2 Hz,
(s, 3H, minor), 3.83 (s, 3H, major), 3.84 (s, 3H, major), 3.85 (s,
methoxybenzyl)chroman-2-yl)phenoxy)phenyl)acrylate (31e). 1H, minor), 5.01 (dd, J = 10.0, 2.0 Hz, 2H, major, minor), 5.15
Following the General Procedure, benzyl acetate 21 (0.071 g, (d, J = 10.2 Hz, 1H, major), 5.23 (d, J = 11.0 Hz, 1H, minor), 6.49
0.16 mmol), compound 29 (0.098 g, 0.33 mmol), and In(OTf)3 (s, 2H, major, minor), 6.52 (s, 1H, major), 6.55 (s, 1H, minor),
(9.2 mg, 0.016 mmol) were employed to give 31e as a white 6.81–6.86 (m, 2H, major, minor), 6.89–6.94 (m, 2H, major,
foam (0.069 g, 0.11 mmol, 66%) of a 5.5:1 mixture of C4- minor), 6.95–7.05 (m, 6H, major, minor), 7.07–7.15 (m, 3H,
1
epimers, favoring the cis C2-C4; H NMR (300 MHz, CDCl3):  major, minor), 7.24 (s, 2H), 7.35–7.44 (m, 5H, major, minor);
1.19 (t, J = 7.1 Hz, 3H, minor), 1.34 (t, J = 7.1 Hz, 3H, major), 13C{1H} NMR (75 MHz, CDCl3):  13.8 (major), 24.2 (major),
2.13–2.26 (m, 2H, major, minor), 2.34 (dd, J = 5.8, 1.8 Hz, 1H, 29.6 (major), 45.5 (major), 45.6 (minor), 55.0 (major), 55.2
major), 2.39 (dd, J = 5.8, 1.7 Hz, 1H, minor), 3.81 (s, 3H, minor), (major), 55.3 (minor), 56.2 (major), 60.5 (major), 77.7 (major),
3.82 (s, 3H, major), 3.85 (s, 3H, major), 3.88 (s, 3H, minor), 79.7 (major), 79.8 (minor), 100.7 (major), 100.8 (minor), 101.1
4.05–4.15 (m, 3H, minor), 4.19–4.25 (m, 1H, minor), 4.26 (q, J (major), 102.0 (major), 103.1 (major), 113.7 (minor), 113.9
= 7.1 Hz, 2H, major), 6.35 (d, J = 16.0 Hz, 1H, major), 6.52 (s, (minor), 114.2 (major), 115.0 (minor), 115.1 (major), 118.5
1H, major), 6.58 (s, 1H, minor), 6.87 (d, J = 8.6 Hz, 4H, major, (major), 118.8 (major), 119.0 (major), 119.1 (minor), 119.1
minor), 6.92 (s, 2H, major, minor), 6.96–7.00 (m, 2H, minor), (minor), 127.6 (major), 128.6 (minor), 128.9 (major), 129.5
6.98 (d, J = 8.7 Hz, 2H, major), 7.03–7.15 (m, 6H, major, minor), (minor), 129.8 (major), 130.1 (minor), 130.3 (minor), 132.7
7.45–7.50 (m, 6H, major, minor), 7.65 (d, J = 16.0 Hz, 2H, (major), 132.7 (major), 133.1 (major), 133.3 (major), 133.8
major, minor); 13C{1H} NMR (75 MHz, CDCl3):  14.3, 40.4, 41.9, (minor), 136.1 (minor), 136.3 (major), 154.7 (major), 154.9
55.3, 56.2, 60.4, 78.2, 101.0, 102.5, 114.2, 117.1, 118.5, 119.5, (major), 155.1 (major), 155.2 (major), 155.3 (minor), 156.4
119.7, 127.8, 129.3, 129.4, 129.7, 133.3, 135.7, 136.5, 143.7, (minor), 156.7 (major), 157.6 (major), 158.9 (major), 169.8
155.2, 155.5, 156.1, 158.6, 159.2, 167.1; TOF-HRMS (m/z): [M (minor), 171.3 (major); TOF-HRMS (m/z): [M + Na+], calcd for
+ H+], calcd for C34H32O679Br, 615.1377; found, 615.1385; calcd C42H38O879Br2Na, 851.0826; found, 851.0812; calcd for
for C34H32O681Br, 617.1359; found, 617.1359.
Ethyl (E)-3-(4-(4-(6-bromo-7-methoxy-4-(4-methoxybenzyl)-3- C42H38O881Br2Na, 855.0798; found, 855.0777.
phenylchroman-2-yl)phenoxy)phenyl)-acrylate (31f). ((6-Bromo-7-methoxy-2-methyl-2,3-diphenylchroman-4-
C42H38O879Br81BrNa, 853.0809; found, 853.0789; calcd for
Following the General Procedure, benzyl acetate 21 (0.071 g, yl)ethynyl)trimethylsilane (34).
0.17 mmol), compound 30 (0.122 g, 0.33 mmol), and PtCl4 Following the General Procedure, benzyl acetate 33 (0.026 g,
(5.54 mg, 0.017 mmol) were employed to give 31f as a white 0.063 mmol), (E)-1,2-diphenylethene 16 (0.023 g, 0.125 mmol),
foam (0.055 g, 0.080 mmol, 48%); 1H NMR (300 MHz, CDCl3):  and In(OTf)3 (0.002 g, 0.003 mmol) were employed to give 34
1.33 (t, J = 7.1 Hz, 3H), 3.22 (t, J = 10.8 Hz, 1H), 3.73 (s, 3H), as a white sticky gum (0.025 g, 0.050 mmol, 79%) of a 10:1
1
3.86 (s, 3H), 4.25 (q, J = 7.1 Hz, 2H), 4.39 (d, J = 11.1 Hz, 1H), mixture of C4-epimers, favoring the cis C2-C4; H NMR (300
5.22 (d, J = 10.5 Hz, 1H), 6.33 (d, J = 16.0 Hz, 1H), 6.58 (s, 1H), MHz, CDCl3):  0.01 (s, 9H), 3.22 (t, J = 10.8 Hz, 1H), 3.84 (s,
6.68 (d, J = 8.7 Hz, 2H), 6.78–6.80 (m, 2H), 6.84 (m, 6H), 6.95 3H), 4.22 (d, J = 10.8 Hz, 1H), 5.12 (d, J = 10.8 Hz, 1H), 6.51 (s,
(d, J = 0.8 Hz, 1H), 7.02–7.06 (m, 3H), 7.18 (d, J = 8.6 Hz, 2H), 1H), 6.97–7.02 (m, 2H), 7.11–7.22 (m, 8H), 7.71 (s, 1H); 13C{1H}
7.44 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 16.0 Hz, 1H); 13C{1H} NMR NMR (75 MHz, CDCl3):  -0.2, 36.8, 51.4, 56.3, 82.6, 88.2,
(75 MHz, CDCl3):  14.3, 48.6, 54.8, 55.1, 56.3, 60.4, 82.6, 100.7, 102.7, 105.2, 115.3, 127.0, 127.3, 128.16, 128.22, 128.5,
100.7, 102.8, 113.7, 116.9, 118.2, 119.4, 120.3, 126.6, 128.2, 132.9, 138.6, 138.7, 154.0, 155.8; TOF-HRMS (m/z): [M + H+],
128.5, 128.9, 129.2, 129.6, 129.8, 133.8, 134.2, 134.9, 139.0, calcd for C28H28O279BrSi, 491.1036; found, 491.0856; calcd for
143.7, 155.1, 155.2, 155.6, 158.2, 159.3, 167.1; TOF-HRMS C28H28O281BrSi, 493.1017; found, 493.1012.
(m/z): [M + H+], calcd for C40H36O679Br, 691.1690; found, ((6-Bromo-7-methoxy-2-(4-methoxyphenyl)-3-
691.1695; calcd for C40H36O681Br, 693.1674; found, 693.1678.
phenylchroman-4-yl)ethynyl)trimethylsilane (35).
Following the General Procedure, benzyl acetate 33 (0.026 g,
0.063 mmol), stilbene 19 (0.026 g, 0.125 mmol), and In(OTf)3
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
(0.002 g, 0.003 mmol) were employed to give 35 as a yellow 3.84 (s, 3H), 6.91 (d, J = 8.8 Hz, 2H), 7.13 (d, J = V1ie6w.3ArtHiczle,O1nHlin)e,
DOI: 10.1039/D0OB01312A
solid (0.032 g, 0.062 mmol, 98%) of a 3:1 mixture of C4- 7.16 (dd, J = 7.8, 7.5 Hz, 1H), 7.30 (dd, J = 7.8, 7.5 Hz, 1H), 7.47
1
epimers, favoring the cis C2-C4; H NMR (400 MHz, CDCl3):  (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 16.3 Hz,
0.02 (s, 9H, major), 0.11 (s, 9H, minor), 3.21 (dd, J = 11.2, 10.5 1H), 7.65 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3): 
Hz, 1H, major), 3.49 (dd, J = 8.7, 4.8 Hz, 1H, minor), 3.71 (s, 3H, 0.05, 55.3, 99.4, 103.7, 114.2, 121.7, 124.7, 126.6, 127.9,
major), 3.73 (s, 3H, minor), 3.82 (s, 3H, major), 3.83 (s, 3H, 128.7, 129.7, 130.2, 132.8, 139.4, 159.5; TOF-HRMS (m/z): [M
minor), 3.92 (d, J = 4.8 Hz, 1H, minor), 4.18 (d, J = 11.2 Hz, 1H, + H+], calcd for C20H23OSi, 307.1513; found, 307.1516.
major), 5.08 (d, J = 10.5 Hz, 1H, major), 5.63 (d, J = 8.7 Hz, 1H, ((6-Bromo-7-methoxy-2-(4-methoxyphenyl)-3-(2-
minor), 6.48 (s, 1H, major), 6.51 (s, 1H, minor), 6.71 (d, J = 8.7 ((trimethylsilyl)ethynyl)phenyl)chroman-4-
Hz, 2H, major), 6.78 (d, J = 8.6 Hz, 2H, minor), 6.98–7.03 (m, yl)ethynyl)trimethylsilane (38).
2H, major), 7.08 (d, J = 8.7 Hz, 2H, major), 7.11–7.15 (m, 2H, Following the General Procedure, benzyl acetate 33 (0.026 g,
minor), 7.15–7.20 (m, 1H, major), 7.20–7.25 (m, 1H, major), 0.063 mmol), stilbene alkyne 36 (0.038 g, 0.125 mmol), and
7.28–7.31 (m, 1H, minor), 7.41 (s, 1H, minor), 7.70 (s, 1H, In(OTf)3 (0.002 g, 0.003 mmol) were reacted at 0–10 °C for 45
major); 13C{1H} NMR (100 MHz, CDCl3):  -0.2 (major), 34.7 min to give 38 as brown sticky gum (0.021 g, 0.035 mmol, 55%)
(minor), 37.1 (major), 47.1 (minor), 51.2 (major), 55.11 along with its C4-epimer 38’ as yellow sticky gum (0.011 g,
1
(major), 55.14 (minor), 56.2 (minor), 56.3 (major), 78.6 0.018 mmol, 28%); H NMR (400 MHz, DMSO-d6, 100 C): 
(minor), 82.1 (major), 88.1 (major), 90.8 (minor), 100.7 0.02 (s, 9H), 0.22 (s, 9H), 3.70 (s, 3H), 3.85 (s, 3H), 3.95 (br t,
(major), 100.8 (minor), 102.3 (minor), 102.5 (major), 105.1 10.7 Hz, 1H), 4.49 (br d, J = 10.7 Hz, 1H), 5.44 (br d, J = 10.7 Hz,
(minor), 105.3 (major), 113.6 (major), 113.8 (minor), 115.3 1H), 6.66 (s, 1H), 6.73 (d, J = 8.7 Hz, 2H), 7.12 (td, J = 7.6, 1.2
9major), 115.5 (minor), 126.9 (major), 127.0 (minor), 127.8 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.26 (dd, J = 7.6, 1.2 Hz, 1H),
(minor), 128.2 (major), 128.5 (major), 128.6 (major), 129.4 7.30 (td, J = 7.6, 1.2 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.57 (d, J =
(minor), 130.7 (major), 131.2 (minor), 132.8 (major), 132.9 1.0 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6, 100 C):  -0.8,
(minor), 138.3 (minor), 139.0 (major), 153.7 (minor), 154.1 35.5 (br), 47.4 (br), 54.6, 56.0, 80.4 (br), 86.7, 97.7 (br), 101.1,
(major), 155.7 (major), 155.9 (minor), 159.3 (major); TOF- 101.2, 104.0, 105.3, 112.9, 115.4, 122.8 (br), 126.0, 127.4 (br),
HRMS (m/z): [M + Na+], calcd for C28H29O379BrSiNa, 543.0962; 128.2, 128.3, 129.9, 131.3, 131.4, 141.0, 153.7, 155.1, 158.7;
found, 543.0959; calcd for C28H29O381BrSiNa, 545.0946; found, TOF-HRMS (m/z): [M + H+], calcd for C33H38O379BrSi, 617.1537;
545.0940.
found, 617.1525; and calcd for C33H38 O381BrSi, 619.1523;
found, 619.1522.
(E)-((2-(4-Methoxystyryl)phenyl)ethynyl)trimethylsilane (36).
Heck Reaction: To a stirred mixture of 2-bromoiodobenzene 37 38’: 1H NMR (300 MHz, CDCl3):  0.06 (s, 9H), 0.20 (s, 9H), 3.74
(0.85 mL, 5.00 mmol), 1-methoxy-4-vinylbenzene 18 (0.78 mL, (s, 3H), 3.84 (s, 3H), 4.08 (d, J = 5.0 Hz, 1H), 4.30 (dd, J = 8.6,
5.85 mmol) and Pd(OAc)2 (0.084 g, 0.38 mmol) in anhydrous 5.0 Hz, 1H), 5.64 (d, J = 8.6 Hz, 1H), 6.50 (s, 1H), 6.80 (d, J = 8.7
MeCN (25 mL) was added Et3N (0.81 mL, 5.85 mmol). The Hz, 2H), 7.04–7.16 (m, 3H), 7.29 (d, J = 8.7 Hz, 2H), 7.37–7.43
reaction was stirred at 90 °C under argon for 20 h. The mixture (m, 3H), 7.45 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3):  -0.13, -
was cooled down to room temperature and concentrated 0.08, 32.6, 43.4, 55.2, 56.2, 78.3, 99.7, 100.8, 102.3, 103.4,
under reduced pressure to give a crude product, which was 105.3, 113.9, 115.5, 123.1, 126.4, 127.7, 128.7, 129.0, 130.9,
further purified by column chromatography on silica (4% 132.2, 132.9, 140.5, 153.7, 155.8, 159.5; TOF-HRMS (m/z): [M
CH2Cl2/hexane) to give the stilbene derivative as a colorless + H+], calcd for C33H38O379BrSi, 617.1537; found, 617.1538; and
solid (1.38 g, 4.75 mmol, 95%); Mp 63.8–65.1 C; 1H NMR (400 calcd for C33H38 O381BrSi, 619.1523; found, 619.1522.
MHz, CDCl3):  3.80 (s, 3H), 6.89 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 6-Bromo-4-ethynyl-3-(2-ethynylphenyl)-7-methoxy-2-(4-
16.2 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), methoxyphenyl)chroman (39).
7.32 (d, J = 16.2 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 7.7 To a solution of the chroman 38 (0.037 g, 0.06 mmol) in
Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): anhydrous THF (0.5 mL) was added TBAF (0.18 mL, 0.18 mmol,
 55.3, 114.1, 123.9, 125.2, 126.4, 127.5, 128.1, 128.3, 129.8, 1.0 M in THF) at 0 °C under argon and the reaction mixture was
130.9, 133.0, 137.3, 159.6; TOF-HRMS (m/z): [M + H+], calcd continued at this temperature for 1 h. The reaction mixture
for C15H14O79BrSi, 289.0223; found, 289.0221; calcd for was quenched with water (0.5 mL) and the resulting mixture
C15H14O81BrSi, 291.0203; found, 291.0198.
was extracted with EtOAc (3 x 1 mL). The combined organic
Sonogashira: To a stirred mixture of the stilbene derivative phases were washed with water (3 x 1 mL) and brine (1 mL),
obtained from the Heck reaction (0.413 g, 1.43 mmol), dried over Na2SO4, filtered, and concentrated under reduced
PdCl2(PPh3)2 (0.060 g, 0.086 mmol and CuI (0.016 g, 0.086 pressure to give a crude product which was further purified by
mmol) in Et3N (0.72 mL) was added trimethylsilylacetylene column chromatography on silica (15% EtOAc/hexane) to give
(0.36 mL, 2.55 mmol). The reaction was stirred at 80 °C under the chroman alkyne 39 as a yellow oil (0.026 g, 0.054 mmol,
1
argon for 24 h. The mixture was cooled down to room 90%); H NMR (400 MHz, DMSO-d6, 100 °C):  2.78 (d, J = 2.4
temperature and concentrated under reduced pressure to give Hz, 1H), 3.69 (s, 3H), 3.83 (s, 3H), 3.94 (br t, J = 10.8 Hz, 1H),
a crude product, which was further purified by column 4.03 (s, 1H), 4.52 (br d, J = 10.8 Hz, 1H), 5.43 (br d, J = 10.8 Hz,
chromatography on silica (0–10% CH2Cl2/hexane) to give the 1H), 6.66 (s, 3H), 6.74 (d, J = 8.6 Hz, 2H), 7.14 (t, J = 7.8 Hz, 1H),
stilbene-alkyne 36 as a yellow solid (0.40 g, 1.30 mmol, 91%); 7.18 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 7.8 Hz, 1H), 3.32 (d, J = 7.8
1
Mp 58.2–60.9 C; H NMR (300 MHz, CDCl3):  0.30 (s, 9H), Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H); 13C{1H} NMR (100
10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
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MHz, DMSO-d6, 100 °C):  34.4 (br), 47.0 (br), 54.6, 56.0, 72.7, 2H), 7.41–7.48 (m, 2H), 7.64–7.71 (m, 1H), 7.85 (Vdie,wJA=rtic8le.7OnHlinze,
80.6 (br), 81.8, 82.5, 83.3, 101.1, 101.3, 112.9, 115.3, 122.1 1H), 7.85–7.89 (m, 1H), 7.934 (d, J = 8.7 DHOz,I:110H.1)0, 379./9D305O(Bs0,1131H2)A;
(br), 126.1, 127.5 (br), 128.3, 129.7, 131.3, 131.9, 140.8, 153.8, 13C{1H} NMR (75 MHz, CDCl3):  55.1, 56.3, 75.8, 102.3, 103.7,
155.2, 158.7; TOF-HRMS (m/z): [M
+
H+], calcd for 113.8, 117.2, 120.0, 122.9, 125.6, 126.0, 126.2, 127.1, 127.5,
C27H22O379Br, 473.0747; found, 473.0738; and calcd for 128.8, 129.1, 129.5, 129.7, 130.9, 132.7, 152.7, 156.8, 159.6;
C27H22O381Br, 475.0730; found, 475.0709.
6-Bromo-7-methoxy-2-(4-methoxyphenyl)-4-vinyl-3-(2-
vinylphenyl)chroman (40).
TOF-HRMS (m/z): [M + H+], calcd for C25H19O379Br, 446.0518;
found, 446.0513; and calcd for C25H19O381Br, 448.0497; found,
448.0490.
A suspension of the chroman alkyne 39 (0.025 g, 0.053 mmol)
and Pd on CaCO3 (0.066 g, 0.033 mmol) in CH2Cl2 (3 mL) was
stirred at room temperature under H2 atmosphere (500 psi).
After being stirred for 18 h, the palladium catalyst was
removed by filtration through Celite® and the filtrate was
concentrated under reduced pressure to give the crude
product, which was further purified by PTLC (20%
EtOAc/hexane, developed twice) to give the diene chroman 40
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the Thailand Research Fund (TRF;
DBG6080007 for P.P.) and Chulabhorn Graduate Scholarship
(for K.A.) is gratefully acknowledged.
1
as a pale yellow sticky gum (0.020 g, 0.041 mmol, 77%); H
NMR (400 MHz, DMSO-d6, 100 °C):  3.55 (dd, J = 11.0, 10.2 Hz,
1H), 3.68 (s, 3H), 3.82 (s, 3H), 3.90 (dd, J = 11.0, 9.1 Hz, 1H),
4.83 (dd, J = 17.0, 1.8 Hz, 1H), 4.95 (dd, J = 10.0, 1.8 Hz, 1H),
5.17 (dd, J = 11.0, 1.6 Hz, 1H), 5.29 (dd, J = 17.2, 1.6 Hz, 1H),
5.31 (d, J = 10.2 Hz, 1H), 5.57 (ddd, J = 17.0, 10.0, 9.1 Hz, 1H),
6.66 (s, 1H), 6.70 (d, J = 8.7 Hz, 2H), 6.86 (dd, J = 17.2, 11.0 Hz,
1H), 7.06 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 7.18 (d, J =
7.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 0.9 Hz, 1H), 7.37
(d, J = 7.8 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6, 100 °C): 
44.3 (br), 47.5, 54.6, 56.0, 81.1, 101.1, 101.3, 112.8, 115.7,
117.3, 118.0, 125.4, 125.7, 127.0, 127.1 (br), 128.1, 130.5,
131.6, 134.7, 137.0, 137.3, 137.6, 154.5, 154.7, 158.5; TOF-
HRMS (m/z): [M + H+], calcd for C27H26O379Br, 477.1060; found,
477.1061; and calcd for C27H26O381Br, 479.1043; found,
479.1069.
Notes and references
1
For review, see: (a) W. Li, X. Xu, P. Zhang and P. Li, Chem.
Asian J., 2018, 13, 2350; (b) C. D.-T. Nielsen, H. Abas and A.
C. Spivey, Synthesis, 2018, 50, 4008; (c) P. Barta, F. Fülöp and
I. Szatmári, Beilstein J. Org. Chem., 2018, 14, 560; (d) D. V.
Osipov, V. A. Osyanin and Y. N. Klimochkin, Russ. Chem. Rev.,
2017, 86, 625; (e) L. Caruana, M. Fochi and L. Bernadi,
Molecules, 2015, 20, 11733; (f) W.-J. Bai, J. G. David, Z.-G.
Feng, M. G. Weaver, K.-L. Wu and T. R. R. Pettus, Acc. Chem.
Res., 2014, 47, 3655; (g) M. S. Singh, A. Nagaraju, N. Anand
and S. Chowdhury, RSC Adv., 2014, 4, 55924; (h) M. M.
Toteva and J. P. Richard, Adv. Phys. Org. Chem., 2011, 45, 39;
(i) F. Dufrasne, M. Gelbcke, J. Neve, R. Kiss and J.-L. Kraus,
Curr. Med. Chem., 2011, 18, 3995.
9-Bromo-8-methoxy-5-(4-methoxyphenyl)-4b,10b-dihydro-
5H-naphtho[1,2-c]chromene (13).
2
3
For some applications in bioorganic chemistry and natural
products, see: (a) J. L. Bolton, T. L. Dunlap and B. M. Dietz,
Food Chem. Toxicol., 2018, 120, 700; (b) Q. Li, T. Dong, X. Liu,
X. Zhang, X. Yang and X. Lei, Curr. Org. Chem., 2014, 18, 86;
(c) Q. Zhou in Quinone Methides, Vol. 1 (Eds.: S. E. Rokita),
Wiley-VCH, Weinheim, 2009, 269; (d) S. E. Rokita in Quinone
Methides, Vol. 1 (Eds.: S. E. Rokita), Wiley-VCH, Weinheim,
2009, 297.
(a) M. Uyanik, K. Nishioka, R. Kondo and K. Ishihara, Nat.
Chem., 2020, 12, 353; (b) L. Burchill, H. P. Pepper, C. J. Sumby
and J. H. George, Org. Lett., 2019, 21, 8304; (c) S.
Mukhopadhyay, C. Gharui and S. C. Pan, Asian J. Org. Chem.,
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47, 7926; (e) R. Chen, Y. Liu and S. Cui, Chem. Commun.,
2018, 54, 11753; (f) N. J. Willis and C. D. Bray, Chem. Eur. J.,
2012, 18, 9160.
Hoveyda-Grubbs’ II catalyst (0.002 g, 0.002 mmol) was added
to a solution of the corresponding diene 40 (0.015 mg, 0.024
mmol) in toluene (2.4 mL). Then, the mixture was heated at 70
C for 24 h. The second portion of Hoveyda-Grubbs’ II catalyst
(0.002 g, 0.002 mmol) was added to the reaction mixture and
heated at 80 C for 24 h. The reaction mixture was evaporated
under reduced pressure. The residue was purified by PTLC
(10% EtOAc/hexane, developed 6 times) to give the desired
chroman 13 as a colorless oil (0.008 g, 0.013 mmol) along with
the naphthochromene byproduct 41 as a colorless oil (0.004 g,
1
0.008 mmol); H NMR (400 MHz, CDCl3):  3.53 (dd, J = 14.7,
10.3 Hz, 1H), 3.65 (br d, J = 14.7 Hz, 1H), 3.80 (s, 3H), 3.85 (s,
3H), 5.34 (d, J = 10.3 Hz, 1H), 6.46 (s, 1H), 6.48 (dd, J = 9.6, 1.9
Hz, 1H), 6.69–6.75 (m, 2H), 6.87–6.95 (m, 1H), 6.98 (d, J = 8.6
Hz, 2H), 7.13–7.17 (m, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.54 (s, 1H);
13C{1H} NMR (100 MHz, CDCl3):  36.2, 41.3, 55.3, 56.2, 80.5,
101.2, 102.5, 114.7, 116.8, 125.7, 126.3, 126.7, 126.9, 129.26,
129.34, 130.1, 131.5, 132.0, 134.8, 135.0, 154.5, 155.2, 160.2;
4
5
6
J.-P. Lumb and D. Trauner, J. Am. Chem. Soc., 2005, 127,
2870.
J.-P. Lumb, K. C. Choong and D. Trauner, J. Am. Chem. Soc.,
2008, 130, 9230.
For isolation, see: (a) A. A. Stierle, D. B. Stierle and K. Kelly, J.
Org. Chem., 2006, 71, 5357. For synthesis, see: (b) C. F.
Bender, F. K. Yoshimoto, C. L. Paradise and J. K. De
Brabander, J. Am. Chem. Soc., 2009, 131, 13350; (c) C. F.
Bender, C. L. Paradise, V. M. Lynch, F. K. Yoshimoto and J. K.
De Brabander, Tetrahedron, 2018, 74, 909; (d) Y. Huang and
T. R. R. Pettus, Synlett, 2008, 9, 1353. For synthesis using
other chemistry, see: (e) F. J. Fañanás, A. Mendoza, T. Arto,
B. Temelli and F. Rodriguez, Angew. Chem. Int. Ed. Engl.,
TOF-HRMS (m/z): [M
+
Na+], calcd for C25H21O379BrNa,
471.0566; found, 471.0565; and calcd for C25H21O381BrNa,
473.0549; found, 473.0570.
1
41: H NMR (300 MHz, CDCl3):  3.70 (s, 3H), 3.84 (s, 3H), 6.50
(s, 1H), 6.73 (d, J = 8.7 Hz, 2H), 7.00 (s, 1H), 7.12 (d, J = 8.7 Hz,
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
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ARTICLE
2012, 51, 4930; (f) Z. E. Wilson and M. A. Brimble, Org.
Journal Name
In(OTf)3 was employed. However, in both caseVsi,ewinAsruticflfeicOinelinnet
Biomol. Chem., 2010, 8, 1284; (g) M. C. McLeod, Z. E. Wilson
and M. A. Brimble, Org. Lett., 2011, 13, 5382; (h) M. C.
McLeod, Z. E. Wilson and M. A. Brimble, J. Org. Chem., 2012, 18 S. Mondal, R. K. Mohamed, M. Manoharan, H. Phan and I. V.
amount of these by-products was obtained, rendering their
DOI: 10.1039/D0OB01312A
complete spectroscopic characterization not possible.
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K.-I. Takao, S. Noguchi, S. Sakamoto, M. Kimura, K. Yoshida
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8
9
10 (a) P. Batsomboon, W. Phakhodee, S. Ruchirawat and P.
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11 For some examples of the use of Fe(II)/Fe(III)-derived
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15 When (Z)-1,2-diphenylethene (i.e. the (Z)-isomer of 16) was
employed for a similar reaction with benzyl acetate 15, the
anticipated corresponding 2,3-cis-diphenylchroman product
was not obtained. (Z)-1,2-diphenylethene could be
recovered unchanged while 15 underwent decomposition
during the reaction. Heating the reaction for 1-18 h gave
similar results with only trace amount of 17 as a product. As
a control experiment, in the absence of 15, no isomerization
of (Z)- to (E)-isomer (i.e. to generate 16) was detected under
the reaction condition. This result suggested that the
stepwise mechanism between 15 and 16 was not a major
reaction pathway for this formal [4+2]-cycloaddition.
16 See the Electronic Supplementary Information (ESI) for the
detailed preparation of compounds 28-30. For the C–O bond
formation of vi, see: M. P. Drapeau, T. Ollevier and M.
Taillefer, Chem. Eur. J., 2014, 20, 5231.
17 When the benzyl acetate 21 reacted with compound 30, 31f
was the sole product when using PTS-Si. Trace amount of
31f’ was obtained when PtCl4 was employed. Interestingly,
trace amount of the product arising from the reaction on the
cinnamate moiety of compound 30 could be detected when
12 | J. Name., 2012, 00, 1-3
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Page 13 of 13
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB01312A
R
R
H
Y
Br
Br
MLn
OAc
MeO
OMOM
+
MeO
O
H
Ar
O
Y
X
Ar
H
H
O
Br
 orthogonality between olefins
 diastereoselectivity with R  H
 15 examples; up to 99% yield
MeO
O
PMP
H
Chemoselective [4+2]-cycloaddition reactions between o-QMs and different olefins—
styrenes, stilbenes, and cinnamates—yielded distinct cycloadducts in moderate to good
yields.