Construction of Sulfonyl Dihydrobenzo[ c]xanthen-7-ones Core via NH4OAc/PdCl2/CuCl2-Mediated Double Cyclocondensation of α-Sulfonyl o-Hydroxyacetophenones with 2-Allylbenzaldehydes

Article abstract of DOI:10.1021/acs.joc.9b02387

NH₄OAc/PdCl₂/CuCl₂ mediated domino double cyclocondensation of α-sulfonyl o-hydroxyacetophenones and 2-allylbenzaldehydes provides tetracyclic sulfonyl dihydrobenzo[c]xanthen-7-one core with good to excellent yields in MeOH. The intermediates contain a 3-sulfonyl flavanone motif. Only water is generated as a byproduct. The use of various catalysts and reaction conditions is studied for the facile-operational conversion.

Full text of DOI:10.1021/acs.joc.9b02387

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Article
Construction of Sulfonyl Dihydrobenzo[c]xanthen-7-ones Core
via NH4OAc/PdCl2/CuCl2-Mediated Double Cyclocondensation of
#-Sulfonyl o-Hydroxyacetophenones with 2-Allylbenzaldehydes
Nai-Chen Hsueh, Min-Chen Tsai, Meng-Yang Chang, and Hsing-Yin Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02387 • Publication Date (Web): 27 Nov 2019
Downloaded from pubs.acs.org on November 28, 2019
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Construction of Sulfonyl Dihydrobenzo[c]xanthen-7-ones Core via
NH4OAc/PdCl2/CuCl2-Mediated Double Cyclocondensation of α-
Sulfonyl o-Hydroxyacetophenones with 2-Allylbenzaldehydes
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Nai-Chen Hsueh,a Min-Chen Tsai,a Meng-Yang Chang*a,b and Hsing-Yin Chen*a
aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan bDepartment of
Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
*Email: mychang@kmu.edu.tw; hychen@kmu.edu.tw
R
O
S
O
O
O
O
S
Me
NH OAc, MeOH, 5 h
4
O
H
R
2
Ar'
2 H O
+
+
Ar'
O
2
O
then PdCl , CuCl , O , 15 h
2
2
2
o
OH
Ar
Ar
one-pot synthesis
mild condition
easy-operational
byproduct is water
ABSTRACT: NH4OAc/PdCl2/CuCl2 mediated domino double cyclocondensation of α-sulfonyl o-hydroxyacetophenones and 2-
allylbenzaldehydes provides tetracyclic sulfonyl dihydrobenzo[c]xanthen-7-one core with good to excellent yields in MeOH. The
intermediates contain a 3-sulfonyl flavanone motif. Only water is generated as a byproduct. The use of various catalysts and reac-
tion conditions is studied for the facile-operational conversion.
Introduction
bond).8 For the straightforward route, organocatalytic aerobic
oxidation of benzylic sp3 C-H bonds of xanthene (recyclable
TEMPO) has been developed by the Wang group.9
Recently, we explore a one-pot facile-operational route for
the preparation of different benzofused carbo- or heterocyclic
skeletons,1 including nitrated or dioxa-benzobicycles,1a-b
Scheme 1. Synthetic Routes of Functionalized Xanthones
tetrahydrocyclobuta[a]naphthalenes,1c
and
benzofused
(Lei, a+b sides)
(Peng, b+c sides)
O
azahomoisotwistanes1d by the concise functionalization of 2-
allylbenzaldehydes (o-allyl benzaldehydes) under cascade
annulation procedures. On the basis of these valuable results,
we plan to construct the core skeleton of xanthone by the com-
bination of 2-allylbenzaldehydes and o-hydroxyacetophenones
under Knoevenagel/Wacker/aldol conditions via a one-step
cascade conversion.
CO
Br
Ar'
+
O
Ar
Ar'
+
OH
Br
Ar
(Wang, oxidation)
(Larock, b+c sides)
O
Pd(II)
ref 3
Pd(II)
ref 4a
TMS
OMe
TEMPO
ref 9
CsF
Ar'
Ar
Ar'
Ar
O
O
+
a
d
b
c
O
OH
TfO
ref 4c
(Zheng, d side)
(Wang, b+d sides)
O
Ar'
Ar
h
Cu(II)
ref 5a
Xanthone is an important structural unit with a wide variety
of natural products and bioactive molecules.2 Accordingly,
there exists a wide selection of methods for the synthesis of
functionalized xanthones via different reagents and catalyst-
promoted intermolecular or/and intramolecular cyclization.
The bond formations for the core pyran-4-one of xanthone can
be divided into two major synthetic types (Scheme 1)3-9 includ-
ing: (1) the intermolecular oxidative double carbonylation of
diaryl ether with carbon monoxide (PdII; a+b bonds),3
cycloannulation of salicylaldehydes with 1,2-dibromoarenes
(PdII; b+c bonds),4a domino coupling-cyclization of salicylates
with arynes (CsF; b+c bonds)4c or ortho-acylation of 2-
nitrobenzaldehydes with phenols (CuII; b+d bonds),5a and (2)
intramolecular cross dehydrogenative coupling (CDC) reaction
of 2-aryloxybenzaldehydes (RhIII; b bond),6a SNAr O-arylation
of 2-bromobenzophenones (CuI; c bond),7a or the photolytic
oxa-6π electrocyclization of benzyliene-1-tetralones (hυ; d
Ar'
O
xanthone (1)
H
ref 8
Ar'
Ar
+
NO
HO
2
Cu(I)
ref 7a
Rh(III)
ref 6a
(Li, b side)
O
(Dominguez, c side)
O
Ar'
Ar
Ar'
Ar
Br
O
OH
However, development of a single-step cascade route for the
simultaneous bond formation and ring-construction of
xanthones from readily available starting materials still repre-
sents a continuing demand in the synthetic chemistry. The
efficient cascade reaction can provide many advantages, espe-
cially in saving of reaction time and reagent cost, and combi-
nation of multiple steps.10 Herein, we report on a one-pot novel
synthesis of tetracyclic dihydrobenzo[c]xanthen-7-ones core (a
xanthone derivative) by NH4OAc/PdCl2/CuCl2-promoted dou-
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ble cyclocondensation of o-hydroxyacetophenones with 2-
6a could not be produced (entry 3). Among the isolated mix-
allylbenzaldehydes via the domino Knoevenagel condensa-
tion/Wacker aerobic oxidation/aldol condensation procedure,
as shown in Scheme 2.11-13 In this reaction fashion, water (2
equiv) is released as the only byproduct.
ture, 7,8-dimethoxynaphthalen-2-ol (54%, by Wacker oxida-
tion of 3a)11a and the starting material 2a (65%) were observed.
Shaw et al. also reported similar observations.15 We speculate
that the basicity of the conjugated bases (acetate ion and chlo-
ride ion) could be a key factor affecting Knoevenagel conden-
sation.12a When PdCl2 was replaced by Pd(OAc)2, 6a was iso-
lated at a 42% yield along with the formation of α-sulfonyl
flavanone 4a (45%) via an incomplete conversion (entry 4). By
elongating the reaction time (15  30 h), the conversion from
4a to 6a could be increased to 1:2 (24% and 54%). The use of
a Pd(dba)2 catalyst decreased the yield of 6a (8%) dramatically
(entry 5). Next, Cu(OAc)2 and CuF2 were examined; however,
both of them provided trace amounts of 6a at low yields (en-
tries 6-7). This meant that CuCl2 was more appropriate than
other copper(II) complexes in the Wacker oxidation of 4a. As
to oxidants, oxone® and K2S2O8, were ineffective for the trans-
formation and provided lower yields of 6a (entries 8-9). In the
comparison of THF and MeOH (entries 10-11), we found that
MeOH was better than both THF and co-solvent of THF and
MeOH (v/v = 1/1) in the generation of 6a within 15 h. By
elongating the reaction time (15  30 h), the conversion from
4a to 6a could be obviously increased. From these results, we
concluded that the combination of NH4OAc/PdCl2/CuCl2 pro-
3
4
5
6
7
8
9
Scheme 2. One-Pot Double Cyclocondensation of α-Sulfonyl
o-Hydroxyacetophenones and 2-Allylbenzaldehydes
R
O
S
H
O
O
O
S
O
Me
10
11
12
13
14
15
16
17
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O
NH OAc then
4
R
Ar'
Ar'
O
3
4
+
O
PdCl , CuCl , O
2
2
2
OH
2
Ar
Ar
3
6
Knoevenagel
condensation
aldol
condensation
- H O
2
- H O
2
O
O
O
Me
O
O
O
Wacker aerobic
oxidation
S
S
O
R
R
Ar'
Ar'
O
O
4
Ar
Ar
5
Results and Discussion
Required starting materials 2 were easily prepared from o-
hydroxyacetophenones following a procedure in literature14
that included α-bromination of o-hydroxyacetophenones fol-
lowed by the nucleophilic substitution of the resulting α-
bromo-o-hydroxyacetophenones with RSO2Na. To examine
the formation of the dihydrobenzo[c]xanthen-7-one core, our
research began on the reaction of model compounds 2a (R =
Tol, Ar’ = Ph, 0.5 mmol) and 3a (Ar = 3,4-(MeO)2Ph, 0.5
mmol) with the NH4OAc (0.8 equiv) in MeOH (3 mL) at re-
flux for 5 h. 3-Sulfonyl flavanone 4a was isolated as a sole
isomer in a 92% yield under the Knoevenagel condensation
conditions. In addition, by the determination of 1H-NMR spec-
trum, two adjacent stereochemical centres of 4a were in trans-
configuration due to the steric hindrance between the allylaryl
and the sulfonyl substituents. In the following step, the reac-
tion of 4a (0.5 mmol) with PdCl2 (10 mol%) and CuCl2 (1.5
o
vided optimal conditions (reflux, 5 h and 25 C, 15 h) in the
presence of an oxygen atmosphere for one-pot construction of
a tetracyclic dihydrobenzo[c]xanthen-7-ones core skeleton.
Table 1. Reaction Conditionsa
Tol
O
S
O
O
O
O
O
S
O
O
Tol
O
O
Me
NH OAc
4
MeOH then
O
S
Tol
+
H
OMe
O
OMe
OMe
+
PdCl , CuCl
2
OH
2
OMe
O
2
OMe
OMe
2a
3a
6a
4a
entry variation from “standard conditions” 6a (%)b 4a (%)b
o
equiv) provided 6a (45%) in MeOH at 25 C for 5 h in the
c
1
2
3
4
5
6
7
8
9
none
85
75
─
─
─
presence of molecular oxygen under Wacker oxidation and
intramolecular aldol condensation procedures. Because MeOH
was the same solvent used for the two steps, a one-pot two-
step synthetic route of the continous reaction was tried. As a
first attempt, PdCl2 and CuCl2 were stepwise added to the re-
sulting reaction mixture of Knoevenagel condensation at 25 oC.
As a result, this one-pot reaction afforded 6a at a better yield
(60%) than a two-step route (41%) because NH4OAc could
promote the intramolecular ring-closure of in-situ formed 5a.
Then, by elongating the reaction time (5  15 and 20 h), the
isolated yields of 6a could be enchanced to 85% and 75%
yields, respectively. However, by elevating the temperature
c
nBu4NOAc, instead of NH4OAc
NH4Cl, instead of NH4OAc
Pd(OAc)2, instead of PdCl2
Pd(dba)2, instead of PdCl2
Cu(OAc)2 instead of CuCl2
CuF2, instead of CuCl2
Oxone, instead of O2
c
c,d
─
42 (51)e 45 (24)e
8
66
70
81
48
66
10
6
20
5
K2S2O8, instead of O2
10 THF, instead of MeOH
46 (72)e 40 (13)e
11 THF/MeOH (1/1), instead of MeOH 63 (80)e 20 (6)e
aThe reactions were performed using a 0.5 mmol scale with 2a,
3a (1.0 equiv), ammonium salt (0.8 equiv), solvent (10 mL), at
reflux for 5 h; then palladium catalyst (10 mol%), copper(II)
o
(25 C  reflux), 6a was obtained in only a 40% yield. From
the above results, it is seen that the combination of NH4OAc,
PdCl2, and CuCl2 in MeOH (standard conditions, Table 1, en-
try 1) gave the best results for the one-pot construction of a
tetracyclic ring system.
o
b
complex (1.5 equiv), at 25 C for 15 h. Isolated yields. cNo
product was observed. d2a (65%) was recovered. e30 h.
Under these conditions, the variations for ammonium salts,
palladium catalysts, copper(II) complexes, co-oxidants, and
reaction solvents were examined, as shown in Table 1, entries
2-11. Initially, the effect of ammonium salts in the formation
of tetracyclic skeleton was examined. However, after elongat-
ing the aliphatic chain (NH4OAc  nBu4NOAc), the yield of
6a (75%) was not enhanced (entry 2). In particular, NH4Cl
could not trigger the Knoevenagel condensation so the desired
To investigate the substrate scope and limitations of the
route, 2 and 3 were treated with the combination of NH4OAc,
PdCl2, and CuCl2 to yield functionalized 6 under molecular
oxygen atmosphere conditions (Table 2). By use of optimal
conditions (Table 1, entry 1), we understood that this cascade
route organized intramolecular double dehydrative annulation
under facile and efficient conditions at good to excellent yields
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(80%-95%). In entries 1-17, the one-pot formation of 6a-6q
By the use of BF3·OEt2/CH2Cl2, the one-pot conversion
2
exhibited that different Ar’ and R (for 2a-2o), and Ar substitu-
ents (for 3a-3c) did not change the distribution of the isolated
yields. For the electronic characteristics of Ar’ substituent on 2,
electron-neutral, electron-withdrawing and electron-donating
groups well-tolerated. For the R substituent of 2, aliphatic (me-
thyl and n-butyl) and aromatic sulfonyl groups were suitable.
Different aryl oxygenated groups (Ar) on 3a-3c were also ap-
propriate to generate core structure 6. Furthermore, the molec-
ular structures of 6b, 6e, 6i and 6q were confirmed by single-
crystal X-ray analysis.16 For the reaction of 2d and 3a, the in-
termediate 6d-1 with a β-hydroxyketone was obtained at a
10% yield (entry 4). In addition, there were trace amounts (5%
and 6%) generated in the formation 6f-1 and 5f (entry 6).
Similar results were observed for 5p (10%, entry 16). The
structures of 6d-1 and 5p were confirmed by single-crystal X-
ray crystallography.16 Although the isolated yields of these
intermediates were low, the generation of tertiary alcohols 6d-
1, 6f-1 and ketones 5f, 5p could properly explain the reaction
pathway.
from the intermediates to the desired dihydrobenzo[c]xanthen-
7-one core could be achieved via a dehydration process. With
these results, different 2-allylbenzaldehydes 3 were examined
next. In particular, when the starting substrate was changed to
3d (Ar = 3-MeOC6H3), only ketone 5r was isolated as the
product at a 94% yield, and the desired tetracyclic 6r was not
3
4
5
6
7
8
9
detected
via
the
NH4OAc/PdCl2/CuCl2-mediated
cyclocondensation of 2a with 3d (Scheme 3, eq 1). On the
other hand, by controlling 3e (Ar = 3-nBuO-5-MeOC6H2) as
the starting material, the uncyclized 5s could be isolated at a
94% yield under similar conditions (eq 2). According to the
resulting data, we found that a C4-oxygenated group on Ar of
3 could play an important role as a substituent in affecting the
intramolecular ring-closure of 5r or 5s. For the relative stereo-
chemistry, 5r and 5s were produced as the sole trans-
10
11
12
13
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1
configurated isomer by the determination of H-NMR spec-
trum. The structural framework of 5s was determined by sin-
gle-crystal X-ray analysis.16 Furthermore, after changing the
methoxy to a hydroxyl group on the C3-position, treatment of
2a with 3f produced 7a at a 90% yield (eq 3). For the for-
mation of β-ketosulfone-conjugated benzofuran (for 7a), A
was formed by Knoevenagel condensation of 2a with 3f in the
initial step. After the aerobic Wacker oxidation of the resulting
A by PdCl2/CuCl2, the C3-hydroxyl group on the in-situ
formed B could promote an intramolecular tandem reaction to
afford the tertiary alcohol C via phenol-methyl ketone annula-
tion, removal of the α-proton, and ring-opening of the
flavanone sequence. Then, aromatization of C led to 7a. Com-
pared with the generation of 6 by intramolecular aldol conden-
sation, the formation of a five-membered ring on C was fa-
vored to preceed. Similarly, the formation of 7b was accom-
plished at a 93% yield by the reaction of 2b with 3f. The struc-
ture of 7a was confirmed by single-crystal X-ray analysis.16
Table 2. Synthesis of 6a
R
O
S
O
O
O
O
S
Me
O
NH OAc, MeOH, 5 h
4
4
5
H
R
Ar'
R
+
Ar'
O
O
3
4
then PdCl , CuCl , O , 15 h
2
2
2
OH
Ar
Ar
5
2
3
6
R
O
O
S
S
O
O
O
O
Me
OH
Me
O
H
H
O
O
Ar
OMe
OMe
6d-1, R = nBu (10%)
6f-1, R = 4-MeOC H (5%)
5f, R = 4-MeOC H , Ar = 3,4-(MeO) C H (6%)
6 4 2 6 2
5p, R = Tol, Ar = 4-MeO-3-nBuOC H (10%)
6
4
6
2
entry 2, Ar’ =, R =
3, Ar =
6, (%)b
6a, 85
6b, 88
6c, 90
6d, 82c
6e, 84
6f, 80d
6g, 84
6h, 87
6i, 90
1
2
3
4
5
6
7
8
9
2a, Ph, Tol
2b, Ph, Ph
2c, Ph, Me
2d, Ph, nBu
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
3a, 3,4-(MeO)2C6H2
Scheme 3. Synthesis of 5r, 5s and 7a-7b
Tol
O
O
S
H
O
O
O
S
Me
O
(eq 1)
O
NH OAc, MeOH, 5 h
Tol
+
4
OMe
O
O
OH
2a
then PdCl , CuCl , O , 15 h
2
2
2
OMe
2e, Ph, 4-FC6H4
3d
5r (94%)
Tol
O
2f, Ph, 4-MeOC6H4
2g, Ph, 3-MeC6H4
2h, Ph, 4-EtC6H4
2i, Ph, 4-iPrC6H4
S
O
O
O
S
O
n
Me
O
(eq 2)
O
Bu
Tol
+
NH OAc, MeOH, 5 h
H
4
O
O
O
OH
2a
then PdCl , CuCl , O , 15 h
2
2
2
n
OBu
3e OMe
5s (94%)
OMe
10 2j, Ph, 4-nBuC6H4
11 2k, Ph, 4-tBuC6H4
12 2l, 4-FC6H3, Tol
6j, 95
6k, 90
6l, 87
O
S
O
R
O
O
O
S
O
H
(E)
OH
NH OAc, MeOH, 5 h
R
+
3
OH
4
(eq 3)
Me
O
OH
then PdCl , CuCl , O , 15 h
2
2
2
OMe
13 2m, 4-MeOC6H3, Tol 3a, 3,4-(MeO)2C6H2
14 2n, 4-Br-2-naphthyl, Tol 3a, 3,4-(MeO)2C6H2
6m, 90
6n, 87
O
3f
2a, R = Tol
2b, R = Ph
7a, R = Tol (90%)
7b, R = Ph (93%)
OMe
R
15 2a, Ph, Tol
3b, 3-iPrO-4-MeOC6H2 6o, 86
3c, 3-nBuO-4-MeOC6H2 6p, 83e
R
O
R
O
S
O
O
O
S
S
O
O
O
O
H
16 2a, Ph, Tol
H
Me
O
H
OH
17 2o, 4-ClC6H3, Tol
3a, 3,4-(MeO)2C6H2
6q, 88
OH
Me
O
O
aThe reactions were performed using a 0.5 mmol scale with
2a-2o, 3a-3h (1.0 equiv), NH4OAc (31 mg, 0.4 mmol) in
MeOH (10 mL), at reflux for 5 h; then PdCl2 (9 mg, 10 mol%),
CuCl2 (100 mg, 0.75 mmol), and O2(g) (1 atm), at 25 oC, 15 h.
O
OH
OH
OMe
OMe
A
B
C
OMe
Density functional theory (DFT) calculations were invoked
to shed some light on the essential role of the C4-oxygenated
group in the intramolecular ring-closure reaction. The ring-
c
d
e
bIsolated yields. 6d-1 (10%). 6f-1 (5%) and 5f (6%). 5p
(10%).
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closure of 5 was assumed to proceed through the elementary
until the formation of III, but significantly lowers the energy
steps depicted at the bottom of Figure 1. The first step is the
deprotonation of C-H connected to the sulfonyl group to form
anionic intermediate I. Then I undergoes an intramolecular
nucleophilic addition (I  II) followed by protonation to form
tetracyclic intermediate III. Notice that this intermediate has
been isolated in experiments (6d-1 and 6f-1). The following
dehydration of III to form the final product 6 was supposed to
be accomplished by the stepwise deprotonation (III  IV) and
protonation (IV  6) processes. Firstly, the free energy
changes of each step mentioned above were calculated for the
5a (R1 = R2 = OMe) and 5r (R1 = OMe, R2 = H) systems, and
the results were compared to extract the effect of C4-
substitution on the ring-closure reaction. However, it turned
out that the calculated energies of each step for 5a and 5r were
very similar (Table 3), which cannot account for different reac-
tion behaviors observed in the two systems. The calculations
showed that while the overall ring-closure reactions were
slightly exergonic, the bottleneck in the reactions occurred at
the second deprotonation step (III  IV); the reaction free
energies of this step were 43.3 and 45.6 kcal/mol for 5a and 5r,
respectively, which are thermodynamically inaccessible (Table
3). These results indicate that only the presence of C3,C4-
oxygenated groups inhibit the promotion of the ring-closure
reaction.
cost for the second deprotonation step (III  IV), rendering
the ring-closure reaction feasible. Mulliken population analysis
revealed that except for the intermediate IV, chelation induces
non-negligible charge polarization from 5a to CuCl2, but the
oxidation state of Cu remains at +2; the negative charge and
spin density on CuCl2 were in the range of |0.296~0.400| and
0.919~0.936 a.u., respectively (Table 4). On the contrary, for
IV the negative charge and spin density on CuCl2 dramatically
increased to 1.036 a.u. and diminished to zero, respectively,
implying that a redox reaction between 5a and CuCl2 occurred
in IV. The electron transfer from 5a to CuCl2 can also be
clearly seen by the spin density plots of III and IV (see Sup-
porting Information, Figure S1). This rationalizes why the
CuCl2 chelation provides abnormally large stabilization for the
deprotonated intermediate IV. Since the copper was reduced to
Cu(I) in IV, the coordination interaction between the two
methoxy groups and CuCl2 was weakend in IV, which can be
evidenced by the longer coordination distance compared to
other intermediates (see Supporting Information, Table S1).
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 make sure that the above-mentioned results are not func-
tional dependent, the ring-closure reactions for 5a and 5a-
CuCl2 were recalculated by using two other popular DFT
methods (see Supporting Information, Figures S2 and S3). All
the three DFT calculations consistently pointed out that the
main effect of CuCl2 chelation is lowering the deprotonation
energy of III  IV. In addition, we also calculated the reac-
tion of 5a-PdCl2, although the PdCl2 was shown to be less
capable of coordinateing with 5a than CuCl2. The results
showed that the PdCl2 can also facilitate the ring-closure reac-
tion by decreasing the energy cost of the second deprotonation
step but is less efficient than the CuCl2 (see Supporting Infor-
mation, Table S2).
We next considered the possible influences of chelation on
the ring-closure reaction as the two methoxy groups in ortho
positions of 5a provide a suitable structural motif to bind with
metal ions. Two metal reagents, PdCl2 and CuCl2, were used in
the one-pot synthesis. To determine which metal reagent had a
higher binding affinity with 5a, the reaction of 5a +
MCl2(MeOH)2  5a-MCl2 + 2MeOH, where M = Pd or Cu
and MeOH is a coordinated solvent molecule, was calculated.
The results showed that the binding of 5a with CuCl2 was
more favorable than with PdCl2; the former was slightly exer-
gonic (G = 1.0 kcal/mol) whereas the latter was slightly
endergonic (G = 1.2 kcal/mol). Accordingly, the effect of
binding with CuCl2 was explored. The free energy changes of
each step involved in the ring-closure reaction were computed
for the 5a-CuCl2 system and compared with 5a (Table 3 and
Figure 1). It can be clearly seen that the presence of CuCl2
displays a relatively minor effect on the energy of the steps
On the basis of the present DFT results, we conclude that
the requirement of a simultaneous presence of two alkoxy
groups at C3 and C4 positions for the ring-closure reaction is
not ascribed to a simple substitution effect, but because the
two alkoxy groups in ortho positions provide a rigid frame-
work to chelate the CuCl2 reagent, which is beneficial for sta-
bilizing the deprotonated intermediate in the ring-closure reac-
tion.
Figure 1. B3LYP-D3/LANL2DZ(Cu)/6-31+G*(H,C,O,S,Cl) Free Energy Profiles (kcal/mol) of the Ring-Closure Reaction for 5a
(black) and 5a-CuCl2 (red).
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Table 3. B3LYP-D3/LANL2DZ(Cu)/6-31+G*(H,C,O,S,Cl)
intramolecular aldol condensation.11a For the major difference
2
3
4
free energy changes (kcal/mol) of the elementary steps in-
volved in the ring-closure reaction.
between β-ketosulfone with β-diketone, we understood that the
sulfonyl group could serve as a fastening substituent to con-
struct the sulfonyl flavanone intermediate such that the tetra-
cyclic core could be established under the aerobic Wacker
oxidation. According to the results, the sulfonyl group played a
key role in constructing the framework of sulfonyl
dihydrobenzo[c]xanthen-7-one core.
5ra
5ab
5a-CuCl2
14.9
5
6
7
8
5  I
14.0
16.9
23.6
45.6
53.6
0.7
14.8
15.7
22.0
43.3
52.6
0.8
I  II
14.1
II  III
III  IV
IV  6
21.2
1.9
9
Scheme 6. Reactions of 2q with 3a, and 2a with 3g
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
Tol
O
O
11.3
1.6
S
O
O
O
S
Tol
Me
O
4
O N
2
O N
2
Overall energy
H
OMe
OMe
O
NH OAc, MeOH, 5 h
4
aR1 = OMe, R2 = H. bR1 = R2 = OMe.
O
(eq 4)
OMe
+
OH
then
PdCl , CuCl , O , 15 h
2
2
2
2q
3a
6t (ND)
OMe
Tol
Table 4. Mulliken charge and spin density on CuCl2 for the
ring-closure reaction of 5a-CuCl2.
O
S
O
O
O
O
S
Tol
Me
O
charge
0.296
0.330
0.400
0.340
1.036
0.362
spin density
0.936
H
NH OAc, MeOH, 5 h
4
OMe
O
(eq 5)
O
+
OH
5
then
4
NO
2
PdCl , CuCl , O , 15 h
2
2
2
OMe
NO
I
0.932
2a
3g
6u (ND)
2
II
III
IV
6
0.919
By adjusting the Ar’ as the electron-withdrawing nitro group,
2q was involved in the above conditions (Scheme 6, eq 4).
When 2q was reacted with 3a, however, no desired 6t was
detected. And, only strating material 2q was recovered (82%)
along with 65% of 10. One possible reason could be that C4-
nitro group of 2q could not promote the electron density effi-
ciently to the para-hydroxy position such that Knoevenagel
condensation occurred more difficultly. On the other way,
exchanging the C4-nitro group from o-hydroxyacetophenone
2q to 2-allylbenzaldehyde 3g was examined next (eq 5). Under
the above conditions, the desired 6u was still not provided by
the treatment of 2a with 3g, and only complex mirture was
observed. Although substrates 2 and 3 was inappropriate to the
electron-withdrawing group, the present route still provided
novel and efficient synthesis of the tetracyclic sulfonyl
dihydrobenzo[c]xanthen-7-one core skeleton.
0.933
0.000
0.931
Scheme 4. Synthesis of 8
Tol
O
O
O
S
O
O
S
O
Tol
+
OH
H
NH OAc, MeOH, 5 h
OMe
OMe
4
O
O
OH
2a
then OsO , NMO, NaIO , 15 h
4
4
OMe
OMe
3a
8 (82%)
In contrast to the formation of 6a, one-carbon diminishing
on the terminal olefin of 3a was examined next. By
OsO4/NMO-mediated double bond-cleavage of the in-situ
generated 4a (derived from Knoevenagel condensation of 2a
and 3a), 8 was isolated at an 82% yield (Scheme 4). Based on
the resulting aldehyde group, only β-hydroxyketone moiety
was formed via the intramolecular aldol procedure. Under the
reaction conditions, no expected dehydrated product was
detected since the secondary alcohol (for 8) was not easier to
eliminate than the tertiary alcohol (for 6a).
Scheme 7. Dehydrosulfonylation of 6a
Tol
O
S
H
O
O
O
Me
Me
dehydrosulfonylation
conditions
O
O
OMe
OMe
OMe
o
#1. tBuOK, THF, 25 C to reflux
6a
11 (ND)
o
OMe
#2. LDA, THF, -78 to 25
o
C
Scheme 5. Synthesis of 9-10
#3. NaH, DME, 25 C to reflux
OH
O
O
O
After producing the sulfonyl dihydrobenzo[c]xanthen-7-one,
construction of oxygenated naphthochromone skeleton18 by the
dehydrosulfonylation of skeleton 6 was studied (Scheme 7).
But, when mode compound 6a was reacted with tBuOK in
O
Ph
+
NH OAc, MeOH, 5 h
4
OMe
OMe
OMe
OMe
+
Ph
O
OH
2p
then
PdCl , CuCl , O , 15 h
2
2
2
3a
9 (82%)
10 (72%)
o
THF at 25 C for 10 h, no reaction was detected. Even after
With optimal reaction conditions, this study examined re-
placing β-ketosulfone with β-diketone, as shown in Scheme 5.
When a one-pot reaction of 2p was treated with 3a in the pres-
ence of NH4OAc, however, the predicted tetracyclic skeleton
could not be obtained, and only 9 and 10 were produced at
82% and 72% yields, respectively. One possible reason could
elongating the time to 30 h and elevating the temperature to
reflux, no reactions were observed. Next, by choosing LDA as
the base to remove the TolSO2H, no desired products were
o
provided (from -78 to 25 C, in THF, 10-30 h), and only the
starting material 6a was recovered. Next, changing the base to
NaH and the solvent to glyme (DME), it was found that there
be
that
intramolecular
cyclocondensation
(Baker-
o
Venkataraman condensation) of 2p itself17 was easier to initi-
ate than intermolecular cyclodehydration of 2p with 3a
(Knoevenagel condensation) such that 3a could be directly
oxidized with PdCl2/CuCl2 to produce 10 at a 72% yield via
was no reaction in the temperature range of 25-85 C (rt 
reflux). The results showed that the benzylic proton on 6a
possessed a great steric hindrance such that the deprotontion
was not preferred to trigger.
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1
2
3
4
5
6
7
8
Scheme 8. Gram-Scale Synthesis of 6a
The reaction mixture was concentrated and extracted with
EtOAc (3 x 60 mL). The combined organic layers were
Tol
O
O
S
O
O
O
S
washed with brine (2 x 10 mL), dried (MgSO4), filtered and
evaporated to afford crude product mixture under reduced
pressure. The remaining mixture was separated by column
chromatography (silica gel, hexanes/EtOAc = 30/1~10/1 as
eluent) affording 4a, 5, 6 and 7.
Me
O
NH OAc, MeOH, 5 h
4
H
OMe
OMe
Tol
+
O
O
then PdCl , CuCl , O , 15 h
2
2
2
OH
OMe
OMe
2a (870 mg, 3 mmol) 3a (620 mg, 3 mmol)
6a (73%, 1.04 g)
Because of the potential application of this protocol in syn-
thesis of tetracyclic sulfonyl dihydrobenzo[c]xanthen-7-ones
core, attempts to scale up the transformation would improve
the significance of the results. Thus, the development of a
gram-scale synthetic method was highly in demand. When the
scale for the NH4OAc/PdCl2/CuCl2-promoted double
cyclocondensation of 2a and 3a increased to 3.0 mmol (870
mg) and 3.0 mmol (620 mg), 6a was isolated in a 73% (1.04 g)
yield, as shown in Scheme 8.
(2S*,3S*)-2-(2-Allyl-3,4-dimethoxyphenyl)-3-tosylchroman-
9
4-one (4a). In Table 1, entry 7. Yield = 81% (194 mg); Color-
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
o
less solid; mp = 145-147 C (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H27O6S
1
479.1528, found 479.1523; H NMR (400 MHz, CDCl3): δ
7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.43
(dt, J = 2.0, 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.94 (dt, J =
0.8, 8.0 Hz, 1H), 6.81 (dt, J = 0.4, 8.0 Hz, 1H), 6.68 (s, 1H),
6.67 (d, J = 8.8 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 6.09-6.00 (m,
1H), 5.12 (dq, J = 1.6, 10.0 Hz, 1H), 5.03 (dq, J = 1.6, 16.8 Hz,
1H), 4.30 (d, J = 0.8 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.74-
3.68 (m, 1H), 3.63-3.57 (m, 1H), 2.38 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 182.7, 159.3, 153.2, 147.9, 145.6, 137.3,
136.3, 134.2, 132.0, 129.5 (2x), 129.3 (2x), 127.5, 126.7,
121.7, 121.4, 120.3, 118.2, 115.8, 109.9, 73.5, 72.6, 60.8, 55.5,
29.9, 21.6.
In conclusion, we have explored a NH4OAc/PdCl2/CuCl2-
promoted one-pot efficient synthesis of tetracyclic sulfonyl
dihydrobenzo[c]xanthen-7-one core system by a domino dou-
ble cyclocondensation of α-sulfonyl o-hydroxyacetophenone
and 2-allylbenzaldehydes in MeOH at good to excellent yields.
Sulfonyl flavanone was the key intermediate. The one-pot
synthetic route produces diversified 4 via a cascade pathway of
one carbon-oxygen and two carbon-carbon bond formations.
The molecular structures of the important products were de-
termined by single-crystal X-ray crystallography. DFT calcula-
tions have been included to shed light on the essential role of
the two alkoxy groups in ortho positions played in the ring-
closure reaction of 5. Further investigations regarding the syn-
thetic application of α-sulfonyl o-hydroxyacetophenones 2 and
2-allylbenzaldehydes 3 are underway in our laboratory.
(6aS*,12aS*)-3,4-Dimethoxy-6-methyl-6a-tosyl-6a,12a-
dihydro-7H-benzo[c]xanthen-7-one (6a). Yield = 85% (202
o
mg); Colorless solid; mp = 129-131 C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C27H25O6S 477.1372, found 477.1380; 1H NMR (400 MHz,
CDCl3): δ 7.97 (dd, J = 2.0, 8.0 Hz, 1H), 7.70 (d, J = 8.4 Hz,
2H), 7.46 (dt, J = 1.6, 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H),
7.08 (q, J = 1.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.04 (dd, J =
1.2, 8.4 Hz, 1H), 6.89 (dd, J = 0.4, 8.4 Hz, 1H), 6.79 (d, J =
8.0 Hz, 1H), 5.90 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.36 (s,
3H), 1.78 (d, J = 1.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 185.5, 161.3, 153.8, 145.0, 144.6, 136.6, 135.0,
131.0 (2x), 128.8 (2x), 128.0, 126.3, 126.2, 124.8, 124.6,
123.2, 122.2, 120.9, 117.8, 111.3, 77.83, 77.52, 61.3, 55.7,
21.56, 21.50.
Experimental Section
General. Commercially available reagents and solvents
were used without further purification. All reactions were car-
ried by standard procedures under an air atmosphere (an open-
vessel condition). All products in EtOAc were dried with an-
hydrous magnesium sulfate before concentration in vacuo un-
der reduced pressure. Melting points (mp) were recorded with
1
a SMP3 melting apparatus. H (400 MHz) and 13C{1H} NMR
(6aS*,12aS*)-3,4-Dimethoxy-6-methyl-6a-(phenylsulfonyl)-
(100 MHz) spectroscopic data were measured on a Varian
INOVA-400 spectrometer, respectively. Chemical shift values
(δ) are reported in ppm relative to CDCl3 as the internal stand-
ards, and coupling contants (J values) are reported in Hertz
(Hz). High-resolution mass spectroscopic data (HRMS) were
measured with a double focusing mass spectrometer by ESI
using a hybrid ion-trap. X-ray single crystal structures were
determined with a diffractometer (CAD4, Kappa CCD).
6a,12a-dihydro-7H-benzo[c]xanthen-7-one (6b). Yield = 88%
o
(203 mg); Colorless solid; mp = 158-160 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
1
calcd for C26H23O6S 463.1215, found 463.1220; H NMR (400
MHz, CDCl3): δ 7.97 (dd, J = 1.6, 7.6 Hz, 1H), 7.84-7.81 (m,
2H), 7.53-7.45 (m, 2H), 7.39-7.35 (m, 2H), 7.10-7.04 (m, 3H),
6.90 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.93 (s, 1H),
3.87 (s, 3H), 3.83 (s, 3H), 1.78 (d, J = 1.6 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 185.5, 161.3, 153.8, 144.6, 137.9,
136.7, 133.8, 131.0 (2x), 128.1 (2x), 128.0, 126.4, 126.3,
124.7, 124.6, 123.0, 122.3, 120.9, 117.8, 111.4, 77.8, 77.6,
61.4, 55.8, 21.4; X-Ray data: compound 6b crystallizes in the
triclinic crystal system, space group P -1, a = 8.9974(4) Å , b =
11.1134(5) Å , c = 12.3498(6) Å , V = 1095.29(9) Å 3, Z = 2,
dcalcd = 1.402 g/cm3, F(000) = 484, 2θ range 1.791~26.439o, R
indices (all data) R1 = 0.0451, wR2 = 0.1058.
For the starting substrates 2 and 3, these compounds were
known and their related analytical data (e.g., HRMS, 1H NMR
and 13C{1H} NMR) were identical with those in the references
19-20.
A representative synthetic procedure of 4a, 5, 6 and 7 is as
follows: NH4OAc (31 mg, 0.4 mmol) was added to a solution
of 2 (0.5 mmol) and 3 (0.5 mmol) in MeOH (10 mL) at 25 oC.
Then, the reaction mixture was refluxed for 5 h. The reaction
was traced by TLC until the starting materials were consumed.
(6aS*,12aS*)-3,4-Dimethoxy-6-methyl-6a-(methylsulfonyl)-
o
6a,12a-dihydro-7H-benzo[c]xanthen-7-one (6c). Yield = 90%
The reaction mixture was cooled to 25 C. Furthermore, PdCl2
o
(180 mg); Colorless solid; mp = 159-161 C (recrystallized
(9 mg, 10 mol%) and CuCl2 (100 mg, 0.75 mmol) were added
to the reaction mixture. Then, molecular oxygen was bubbled
into the mixture for 2 h, and stirring occurred at 25 oC for 15 h.
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
1
calcd for C21H21O6S 401.1059, found 401.1063; H NMR (400
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The Journal of Organic Chemistry
MHz, CDCl3): δ 8.00 (dd, J = 2.0, 8.0 Hz, 1H), 7.51 (dt, J =
dcalcd = 1.467 g/cm3, F(000) = 848, 2θ range 1.802~26.492o, R
2
3
4
5
6
7
8
9
2.0, 8.8 Hz, 1H), 7.24 (br s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.09
(dt, J = 0.8, 8.0 Hz, 1H), 6.95 (dd, J = 0.4, 8.4 Hz, 1H), 6.89 (d,
J = 8.4 Hz, 1H), 5.90 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.10 (s,
3H), 2.02 (d, J = 1.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 186.4, 161.5, 154.2, 145.0, 137.1, 128.0, 127.3,
126.4, 124.4, 123.0, 122.9, 122.4, 120.3, 117.9, 111.6, 76.7,
76.3, 61.5, 55.7, 42.3, 21.3.
indices (all data) R1 = 0.0534, wR2 = 0.1142.
(6aS*,12aS*)-3,4-Dimethoxy-6a-((4-
methoxyphenyl)sulfonyl)-6-methyl-6a,12a-dihydro-7H-
benzo[c]xanthen-7-one (6f). Yield = 80% (197 mg); Colorless
liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H25O7S
1
493.1321, found 493.1326; H NMR (400 MHz, CDCl3): δ
7.97 (dd, J = 2.0, 8.0 Hz, 1H), 7.74 (d, J = 9.2 Hz, 2H), 7.46
(dt, J = 1.6, 8.8 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 7.04 (dd, J =
0.4, 8.0 Hz, 1H), 6.89 (dd, J = 0.4, 8.4 Hz, 1H), 6.82 (d, J =
8.8 Hz, 2H), 6.80 (dd, J = 0.4, 8.4 Hz, 1H), 5.90 (s, 1H), 3.87
(s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 1.78 (d, J = 1.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 185.6, 163.9, 161.3,
153.7, 144.6, 136.6, 133.2 (2x), 129.2, 128.0, 126.2, 126.1,
125.0, 124.6, 123.3, 122.2, 120.9, 117.8, 113.3 (2x), 111.4,
77.9, 77.4, 61.3, 55.7, 55.6, 21.5.
(6aS*,12aS*)-6a-(n-Butylsulfonyl)-3,4-dimethoxy-6-methyl-
6a,12a-dihydro-7H-benzo[c]xanthen-7-one (6d). Yield = 82%
(181 mg); Colorless solid; mp = 68-70 oC (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C24H27O6S 443.1528, found 443.1536; 1H NMR (400 MHz,
CDCl3): δ 7.99 (dd, J = 2.0, 8.0 Hz, 1H), 7.51 (dt, J = 1.6, 8.8
Hz, 1H), 7.22 (d, J = 1.2 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H),
7.09 (dt, J = 0.8, 8.0 Hz, 1H), 6.95 (dd, J = 0.8, 8.4 Hz, 1H),
6.88 (d, J = 8.4 Hz, 1H), 5.92 (s, 1H), 3.89 (s, 3H), 3.88 (s,
3H), 3.75-3.67 (m, 1H), 3.13-3.06 (m, 1H), 2.01 (d, J = 1.2 Hz,
3H), 1.86-1.74 (m, 2H), 1.48-1.39 (m, 2H), 0.91 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 186.9, 161.6, 154.0,
144.9, 137.1, 128.0, 127.3, 126.3, 124.3, 123.3, 122.8, 122.3,
120.5, 118.0, 111.5, 76.8, 76.7, 61.5, 55.7, 53.7, 22.3, 21.9,
21.6, 13.6.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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(6R*,6aR*,12aS*)-6-Hydroxy-3,4-dimethoxy-6a-((4-
methoxyphenyl)sulfonyl)-6-methyl-5,6,6a,12a-tetrahydro-7H-
benzo[c]xanthen-7-one (6f-1). Yield = 5% (13 mg); Colorless
solid; mp = 164-166 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H27O8S
1
511.1427, found 511.1435; H NMR (400 MHz, CDCl3): δ
7.72 (dd, J = 1.6, 8.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.20
(dt, J = 1.6, 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.85 (d, J =
7.6 Hz, 1H), 6.71-6.66 (m, 3H), 6.41 (s, 1H), 6.31 (d, J = 8.0
Hz, 1H), 4.50 (br s, 1H), 3.80 (s, 3H), 3.74 (s, 6H), 3.10 (d, J =
18.0 Hz, 1H), 2.97 (d, J = 18.4 Hz, 1H), 2.26 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 183.8, 164.2, 157.9, 152.2, 145.8,
136.5, 132.1 (2x), 131.5, 130.7, 130.0, 127.0, 124.8, 122.0,
121.72, 121.69, 117.9, 114.1, 113.2, 111.0, 76.2, 75.7, 60.0,
55.7, 55.5, 37.2, 29.2.
(6R*,6aR*,12aS*)-6a-(n-Butylsulfonyl)-6-hydroxy-3,4-
dimethoxy-6-methyl-5,6,6a,12a-tetrahydro-7H-
benzo[c]xanthen-7-one (6d-1). Yield = 10% (23 mg); Color-
o
less solid; mp = 190-192 C (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H29O7S
1
461.1634, found 461.1630; H NMR (400 MHz, CDCl3): δ
7.80 (dd, J = 2.0, 8.0 Hz, 1H), 7.48 (dt, J = 1.6, 8.4 Hz, 1H),
7.33 (dd, J = 0.8, 8.8 Hz, 1H), 7.00 (dd, J = 0.8, 8.4 Hz, 1H),
6.94 (dt, J = 1.2, 8.0 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.45 (s,
1H), 5.00 (br s, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.64-3.56 (m,
1H), 3.49-3.41 (m, 1H), 3.14 (d, J = 17.6 Hz, 1H), 2.86 (d, J =
17.6 Hz, 1H), 1.95-1.85 (m, 2H), 1.52-1.43 (m, 2H), 1.46 (d, J
= 0.8 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 191.2, 159.3, 152.3, 145.3, 137.9, 129.5 (2x),
127.0, 124.1, 123.0, 122.0, 119.2, 111.7, 75.9, 75.8, 74.2, 60.1,
56.8, 55.6, 39.8, 22.65, 22.57, 21.9, 13.6; X-Ray data: com-
pound 6d-1 crystallizes in the orthorhombic crystal system,
space group P n a 21, a = 17.864(4) Å , b = 15.417(4) Å , c =
7.9315(18) Å , V = 2184.5(9) Å 3, Z = 4, dcalcd = 1.400 g/cm3,
F(000) = 976, 2θ range 1.745~26.357o, R indices (all data) R1
= 0.0500, wR2 = 0.0925.
(2S*,3S*)-2-(3,4-Dimethoxy-2-(2-oxopropyl)phenyl)-3-((4-
methoxyphenyl)sulfonyl)chroman-4-one (5f). Yield = 6% (15
o
mg); Colorless solid; mp = 179-181 C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C27H27O8S 511.1427, found 511.1430; 1H NMR (400 MHz,
CDCl3): δ 7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.71 (d, J = 8.8 Hz,
2H), 7.42 (dt, J = 2.0, 8.4 Hz, 1H), 6.94 (dt, J = 1.2, 8.0 Hz,
1H), 6.91 (d, J = 9.2 Hz, 2H), 6.72 (dd, J = 0.4, 8.4 Hz, 1H),
6.68 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H),
4.37 (d, J = 0.8 Hz, 1H), 4.09 (s, 2H), 3.84 (s, 3H), 3.76 (s,
3H), 3.75 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 205.7, 182.8, 164.3, 158.7, 153.1, 148.1, 142.0,
137.4, 131.6 (2x), 128.5, 127.6, 126.7, 121.8, 121.7, 120.3,
118.4, 114.2 (2x), 110.6, 73.7, 72.0, 60.5, 55.7, 55.5, 41.3,
30.1.
(6aS*,12aS*)-6a-((4-Fluorophenyl)sulfonyl)-3,4-dimethoxy-
6-methyl-6a,12a-dihydro-7H-benzo[c]xanthen-7-one
(6e).
Yield = 84% (202 mg); Colorless solid; mp = 152-154 oC (re-
(6aS*,12aS*)-3,4-Dimethoxy-6-methyl-6a-(m-tolylsulfonyl)-
6a,12a-dihydro-7H-benzo[c]xanthen-7-one (6g). Yield = 84%
(200 mg); Colorless liquid; HRMS (ESI-TOF) m/z: [M + H]+
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C26H22FO6S 481.1121, found 481.1129; H
1
1
NMR (400 MHz, CDCl3): δ 7.97 (dd, J = 1.6, 8.0 Hz, 1H),
7.85-7.81 (m, 2H), 7.48 (dt, J = 2.0, 9.2 Hz, 1H), 7.09-7.01 (m,
5H), 6.90 (dd, J = 0.4, 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H),
5.91 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 1.77 (d, J = 1.6 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 185.4, 165.9 (d, J =
256.2 Hz), 161.3, 153.9 (2x), 144.7, 136.8, 133.8 (d, J = 9.9
Hz, 2x), 128.0, 126.4, 126.1, 124.59, 124.57, 123.3, 122.3,
120.8, 117.8, 115.3 (d, J = 21.9 Hz, 2x), 111.6, 77.7, 77.6,
61.3, 55.8, 21.4; X-Ray data: compound 6e crystallizes in the
monoclinic crystal system, space group P 21/c, a = 10.8679(10)
Å , b = 22.598(2) Å , c = 9.3473(8) Å , V = 2174.9(4) Å 3, Z = 4,
calcd for C27H25O6S 477.1372, found 477.1378; H NMR (400
MHz, CDCl3): δ 7.98 (dd, J = 2.0, 8.0 Hz, 1H), 7.60 (d, J = 7.6
Hz, 1H), 7.57 (s, 1H), 7.47 (dt, J = 2.0, 8.4 Hz, 1H), 7.28 (d, J
= 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.08-7.04 (m, 3H),
6.89 (dd, J = 0.4, 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.91 (s,
1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.33 (s, 3H), 1.86 (d, J = 1.6
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 185.3, 161.2,
153.7, 144.6, 138.2, 137.5, 136.6, 134.6, 131.2, 128.2, 128.1,
127.9, 126.3, 126.2, 124.9, 124.6, 123.0, 122.2, 121.0, 117.7,
111.3, 77.9, 77.6, 61.3, 55.8, 21.5, 21.3.
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(6aS*,12aS*)-6a-((4-Ethylphenyl)sulfonyl)-3,4-dimethoxy-
185.3, 161.3, 157.8, 153.6, 144.4, 136.6, 134.7, 130.8 (2x),
128.1, 126.3, 126.0, 125.2, 125.1 (2x), 124.7, 123.0, 122.2,
121.1, 117.7, 111.1, 78.0, 77.5, 61.2, 55.5, 35.2, 30.9 (3x),
21.5.
6-methyl-6a,12a-dihydro-7H-benzo[c]xanthen-7-one
(6h).
Yield = 87% (213 mg); Colorless solid; mp = 146-148 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
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[M + H]+ calcd for C28H27O6S 491.1528, found 491.1532; H
(6aS*,12aS*)-9-Fluoro-3,4-dimethoxy-6-methyl-6a-tosyl-
NMR (400 MHz, CDCl3): δ 7.98 (dd, J = 1.6, 8.0 Hz, 1H),
7.71 (d, J = 8.4 Hz, 2H), 7.46 (dt, J = 2.0, 9.2 Hz, 1H), 7.17 (d,
J = 8.4 Hz, 2H), 7.08-7.03 (m, 3H), 6.89 (dd, J = 0.8, 8.4 Hz,
1H), 6.77 (d, J = 8.4 Hz, 1H), 5.91 (s, 1H), 3.85 (s, 3H), 3.82
(s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1.81 (d, J = 1.6 Hz, 3H), 1.21
(t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 185.4,
161.3, 153.7, 151.0, 144.5, 136.6, 135.1, 131.0 (2x), 128.0,
127.6 (2x), 126.3, 126.1, 124.9, 124.6, 123.1, 122.2, 120.9,
117.8, 111.2, 77.9, 77.5, 61.2, 55.6, 28.8, 21.5, 14.9.
6a,12a-dihydro-7H-benzo[c]xanthen-7-one (6l). Yield = 87%
o
(215 mg); Colorless solid; mp = 130-132 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C27H24FO6S 495.1278, found 495.1283; 1H NMR
(400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz, 2H), 7.61 (dd, J =
3.2, 8.4 Hz, 1H), 7.19 (dt, J = 3.2, 7.6 Hz, 1H), 7.16 (d, J = 8.0
Hz, 2H), 7.09 (q, J = 1.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H),
6.89 (dd, J = 4.4, 9.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.88 (s,
1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.36 (s, 3H), 1.77 (d, J = 1.2
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 185.0, 157.7,
157.5 (d, J = 241.8 Hz), 153.9, 145.2, 144.6, 134.7, 131.0 (2x),
128.8 (2x), 126.3, 126.2, 124.6, 124.5, 124.2, 122.9, 119.7,
119.6, 112.9, 112.7, 111.3, 78.2, 61.3, 55.7, 21.6, 21.5.
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(6aS*,12aS*)-6a-((4-Isopropylphenyl)sulfonyl)-3,4-
dimethoxy-6-methyl-6a,12a-dihydro-7H-benzo[c]xanthen-7-
one (6i). Yield = 90% (227 mg); Colorless solid; mp = 164-
166 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C29H29O6S 505.1685, found
505.1693; 1H NMR (400 MHz, CDCl3): δ 7.99 (dd, J = 1.6, 8.0
Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.46 (dt, J = 1.6, 8.4 Hz,
1H), 7.17 (d, J = 8.4 Hz, 2H), 7.08-7.02 (m, 3H), 6.88 (d, J =
8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.92 (s, 1H), 3.84 (s,
3H), 3.81 (s, 3H), 2.92-2.85 (m, 1H), 1.85 (d, J = 1.6 Hz, 3H),
1.205 (d, J = 6.8 Hz, 3H), 1.203 (d, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 185.3, 161.3, 155.5, 153.7, 144.4,
136.6, 135.1, 131.1 (2x), 128.1, 126.3, 126.2 (2x), 126.0,
125.1, 124.6, 123.0, 122.2, 121.0, 117.8, 111.2, 77.9, 77.5,
61.2, 55.6, 34.2, 23.5, 23.4, 21.5; X-Ray data: compound 6i
crystallizes in the monoclinic crystal system, space group P
21/c, a = 10.1806(11) Å , b = 22.707(2) Å , c = 11.1057(13) Å ,
V = 2446.3(5) Å 3, Z = 4, dcalcd = 1.370 g/cm3, F(000) = 1064,
2θ range 2.099~26.458o, R indices (all data) R1 = 0.0414, wR2
= 0.0909.
(6aS*,12aS*)-3,4,10-Trimethoxy-6-methyl-6a-tosyl-6a,12a-
dihydro-7H-benzo[c]xanthen-7-one (6m). Yield = 90% (228
o
mg); Colorless solid; mp = 116-118 C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C28H27O7S 507.1478, found 507.1485; 1H NMR (400 MHz,
CDCl3): δ 7.90 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H),
7.17 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H),
6.80 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 2.0, 8.4 Hz, 1H), 6.33 (d,
J = 2.4 Hz, 1H), 5.89 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.78 (s,
3H), 2.36 (s, 3H), 1.75 (d, J = 1.6 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 183.8, 166.5, 163.3, 153.8, 144.9, 144.6,
135.2, 131.0 (2x), 129.8, 129.0, 128.8 (2x), 126.4, 125.9,
125.2, 124.4, 123.3, 111.4, 111.2, 100.2, 78.0, 77.5, 61.3,
55.74, 55.70, 21.6, 21.5.
(6aS*,14aS*)-9-Bromo-3,4-dimethoxy-6-methyl-6a-tosyl-
6a,14a-dihydro-7H-dibenzo[c,h]xanthen-7-one (6n). Yield =
87% (263 mg); Colorless liquid; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C31H26BrO6S 605.0634, found 605.0640; 1H
NMR (400 MHz, CDCl3): δ 8.20 (s, 1H), 8.17 (d, J = 8.0 Hz,
1H), 8.12 (dd, J = 0.8, 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H),
7.71 (dd, J = 0.8, 8.0 Hz, 1H), 7.51 (dt, J = 0.8, 8.0 Hz, 1H),
7.18 (d,, J = 8.0 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.11 (br q, J
= 0.8 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 3.91 (s,
3H), 3.86 (s, 3H), 2.36 (s, 3H), 1.79 (d, J = 1.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 183.9, 159.6, 154.0,
145.2, 144.6, 135.5, 134.8, 131.4, 131.0 (2x), 128.9 (2x),
127.5, 127.2, 126.6, 126.3, 125.4, 125.3, 124.8, 124.6, 124.2,
122.8, 116.1, 115.6, 111.3, 78.9, 77.3, 61.3, 55.8, 21.6, 21.5.
(6aS*,12aS*)-6a-((4-n-Butylphenyl)sulfonyl)-3,4-
dimethoxy-6-methyl-6a,12a-dihydro-7H-benzo[c]xanthen-7-
one (6j). Yield = 95% (246 mg); Colorless solid; mp = 103-
105 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C30H31O6S 519.1841, found
519.1849; 1H NMR (400 MHz, CDCl3): δ 7.97 (dd, J = 1.6, 8.0
Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.46 (dt, J = 2.0, 9.2 Hz,
1H), 7.16 (d, J = 8.4 Hz, 2H), 7.09-7.03 (m, 3H), 6.89 (d, J =
8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.92 (s, 1H), 3.86 (s,
3H), 3.83 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 1.79 (d, J = 1.2 Hz,
3H), 1.57-1.51 (m, 2H), 1.36-1.25 (m, 2H), 0.93 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 185.5, 161.3, 153.7,
149.9, 144.5, 136.6, 135.1, 131.0 (2x), 128.1 (2x), 128.0,
126.3, 126.1, 124.9, 124.6, 123.1, 122.2, 120.9, 117.8, 111.2,
77.8, 77.5, 60.3, 55.7, 35.6, 33.0, 22.3, 21.5, 13.9.
(6aS*,12aS*)-4-Isopropoxy-3-methoxy-6-methyl-6a-tosyl-
6a,12a-dihydro-7H-benzo[c]xanthen-7-one (6o). Yield = 86%
(217 mg); Colorless liquid; HRMS (ESI-TOF) m/z: [M + H]+
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(6aS*,12aS*)-6a-((4-(tert-Butyl)phenyl)sulfonyl)-3,4-
calcd for C29H29O6S 505.1685, found 505.1690; H NMR (400
dimethoxy-6-methyl-6a,12a-dihydro-7H-benzo[c]xanthen-7-
one (6k). Yield = 90% (233 mg); Colorless solid; mp = 165-
167 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C30H31O6S 519.1841, found
519.1847; 1H NMR (400 MHz, CDCl3): δ 7.99 (dd, J = 1.6, 8.0
Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.46 (dt, J = 2.0, 9.2 Hz,
1H), 7.33 (d, J = 8.4 Hz, 2H), 7.07-7.06 (m, 2H), 7.03 (d, J =
8.0 Hz, 1H), 6.88 (dd, J = 0.4, 8.0 Hz, 1H), 6.74 (d, J = 8.4 Hz,
1H), 5.93 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 1.86 (d, J = 1.6
Hz, 3H), 1.27 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ
MHz, CDCl3): δ 7.94 (dd, J = 1.6, 8.0 Hz, 1H), 7.76 (d, J = 8.4
Hz, 2H), 7.46 (dt, J = 1.6, 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz,
2H), 7.15 (br t, J = 0.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 7.04
(dt, J = 0.8, 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.81 (d, J =
8.0 Hz, 1H), 5.90 (s, 1H), 4.47-4.41 (m, 1H), 3.86 (s, 3H), 2.39
(s, 3H), 1.67 (d, J = 1.2 Hz, 3H), 1.36 (d, J = 6.0 Hz, 3H), 1.32
(d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 185.9,
161.4, 154.0, 145.0, 142.8, 136.6, 135.5, 131.0 (2x), 128.8
(2x), 127.9, 127.5, 127.4, 123.9, 123.6, 123.3, 122.1, 120.8,
117.8, 111.2, 77.8, 77.6, 75.6, 55.7, 22.6, 22.5, 21.6, 21.5.
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8.0 Hz, 2H), 6.98 (d, J = 7.6 Hz, 1H), 6.93 (dt, J = 0.8, 8.0 Hz,
1H), 6.89 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.70 (d, J = 8.0 Hz,
1H), 6.52 (s, 1H), 4.39 (d, J = 1.2 Hz, 1H), 3.67 (s, 3H), 3.57
(d, J = 0.4 Hz, 2H), 2.37 (s, 3H), 2.09 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 206.1, 182.0, 158.9, 157.7, 145.7, 137.3,
136.6, 134.1, 131.5, 129.5 (2x), 129.4 (2x), 126.9, 124.3,
121.7, 120.8, 118.12, 118.09, 108.4, 76.2, 72.9, 55.3, 44.8,
29.4, 21.6.
6a,12a-dihydro-7H-benzo[c]xanthen-7-one (6p). Yield = 83%
(215 mg); Colorless liquid; HRMS (ESI-TOF) m/z: [M + H]+
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calcd for C30H31O6S 519.1841, found 519.1848; H NMR (400
MHz, CDCl3): δ 7.96 (dd, J = 2.0, 8.0 Hz, 1H), 7.71 (d, J = 8.4
Hz, 2H), 7.46 (dt, J = 1.6, 8.4 Hz, 1H), 7.17 (d, J = 8.0 Hz,
2H), 7.10 (d, J = 1.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.89 (dd, J =
0.4, 8.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.90 (s, 1H), 3.95 (t,
J = 6.8 Hz, 2H), 3.85 (s, 3H), 2.37 (s, 3H), 1.80-1.74 (m, 2H),
1.74 (d, J = 1.2 Hz, 3H), 1.57-1.48 (m, 2H), 1.00 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 185.7, 161.3, 153.9,
145.0, 144.0, 136.6, 135.1, 131.0 (2x), 128.8 (2x), 128.0,
126.7, 126.5, 124.3, 124.2, 123.2, 122.2, 120.9, 117.8, 111.3,
77.8, 77.6, 73.6, 55.7, 32.2, 21.59, 21.56, 19.2, 13.9.
(2S*,3S*)-2-(3-n-Butoxy-5-methoxy-2-(2-
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oxopropyl)phenyl)-3-tosylchroman-4-one (5s). Yield = 94%
o
(252 mg); Colorless solid; mp = 141-143 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
1
calcd for C30H33O7S 537.1947, found 537.1943; H NMR (400
MHz, CDCl3): δ 7.72-7.69 (m, 3H), 7.41 (dt, J = 1.6, 8.4 Hz,
1H), 7.22 (d, J = 8.4 Hz, 2H), 6.93 (dt, J = 1.2, 8.0 Hz, 1H),
6.88 (d, J = 8.4 Hz, 1H), 6.49 (s, 1H), 6.34 (s, 2H), 4.39 (d, J =
0.8 Hz, 1H), 3.81-3.69 (m, 2H), 3.62 (s, 3H), 3.59 (s, 2H), 2.36
(s, 3H), 2.05 (s, 3H), 1.64-1.57 (m, 2H), 1.42-1.33 (m, 2H),
0.89 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
206.7, 182.0, 159.0, 158.4, 157.8, 145.7, 137.3, 136.4, 134.1,
129.5 (2x), 129.4 (2x), 126.9, 121.7, 120.8, 118.0, 112.7,
102.5, 101.4, 76.5, 73.0, 68.0, 55.6, 38.2, 31.0, 29.2, 21.6, 19.1,
13.7; X-Ray data: compound 5s crystallizes in the triclinic
crystal system, space group P -1, a = 12.6557(11) Å , b =
14.4552(12) Å , c = 16.5189(15) Å , V = 2781.4(4) Å 3, Z = 2,
dcalcd = 1.281 g/cm3, F(000) = 1136, 2θ range 1.530~26.487o, R
indices (all data) R1 = 0.0996, wR2 = 0.1882.
(2S*,3S*)-2-(3-n-Butoxy-4-methoxy-2-(2-
oxopropyl)phenyl)-3-tosylchroman-4-onee (5p). Yield = 10%
(27 mg); Colorless solid; mp = 179-181 oC (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C30H33O7S 537.1947, found 537.1942; 1H NMR (400 MHz,
CDCl3): δ 7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.67 (d, J = 8.4 Hz,
2H), 7.41 (dt, J = 1.6, 8.4 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H),
6.93 (dt, J = 1.2, 8.0 Hz, 1H), 6.72 (dd, J = 0.8, 8.4 Hz, 1H),
6.66 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H),
4.38 (d, J = 0.8 Hz, 1H), 4.11 (s, 2H), 3.88 (dt, J = 2.4, 8.0 Hz,
2H), 3.73 (s, 3H), 2.39 (s, 3H), 2.37 (s, 3H), 1.70-1.63 (m, 2H),
1.48-1.39 (m, 2H), 0.95 (t, J = 7.6 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 205.6, 182.6, 158.8, 153.1, 147.5, 145.6,
137.4, 134.2, 129.6 (2x), 129.3 (2x), 128.3, 127.6, 126.6,
121.6, 121.4, 120.3, 118.3, 110.5, 73.5, 72.7, 71.8, 55.5, 41.5,
32.3, 30.0, 21.6, 19.1, 13.8; X-Ray data: compound 5p
crystallizes in the monoclinic crystal system, space group P
21/c, a = 16.7195(5) Å , b = 15.7342(5) Å , c = 10.2217(3) Å , V
= 2688.96(14) Å 3, Z = 4, dcalcd = 1.326 g/cm3, F(000) = 1136,
2θ range 1.218~26.497o, R indices (all data) R1 = 0.0420, wR2
= 0.0854.
(E)-1-(2-Hydroxyphenyl)-3-(7-methoxy-2-
methylbenzofuran-4-yl)-2-tosylprop-2-en-1-one (7a). Yield =
o
90% (208 mg); Colorless solid; mp = 154-156 C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C26H23O6S 463.1215, found 463.1224; H NMR
(400 MHz, CDCl3): δ 7.73-7.71 (m, 3H), 7.39 (dt, J = 1.6, 8.8
Hz, 1H), 7.24 (d, J = 7.6 Hz, 2H), 6.91 (dt, J = 0.8, 8.0 Hz,
1H), 6.83 (dd, J = 0.4, 8.4 Hz, 1H), 6.76 (s, 1H), 6.69 (dd, J =
0.4, 8.4 Hz, 1H), 6.64 (d, J = 1.2 Hz, 1H), 6.46 (d, J = 8.0 Hz,
1H), 4.46 (d, J = 1.2 Hz, 1H), 3.88 (s, 3H), 2.50 (d, J = 1.2 Hz,
3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.4,
158.9, 156.6, 145.6, 145.3, 143.9, 137.2, 134.3, 129.5 (2x),
129.3 (2x), 128.8, 126.8, 121.6, 120.5, 120.4, 119.8, 118.1,
104.6, 101.6, 74.7, 71.9, 55.9, 21.6, 14.1; X-Ray data: com-
pound 7a crystallizes in the monoclinic crystal system, space
group P 21/c, a = 10.8962(7) Å , b = 16.0021(8) Å , c =
14.7675(9) Å , V = 2500.4(3) Å 3, Z = 4, dcalcd = 1.229 g/cm3,
F(000) = 968, 2θ range 1.907~26.425o, R indices (all data) R1
= 0.0609, wR2 = 0.1106.
(6aS*,12aS*)-9-Chloro-3,4-dimethoxy-6-methyl-6a-tosyl-
6a,12a-dihydro-7H-benzo[c]xanthen-7-one (6q). Yield = 88%
o
(224 mg); Colorless solid; mp = 155-157 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
1
calcd for C27H24ClO6S 511.0982, found 511.0986; H NMR
(400 MHz, CDCl3): δ 7.92 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 8.4
Hz, 2H), 7.39 (dd, J = 2.4, 8.8 Hz, 1H), 7.16 (d, J = 8.0 Hz,
2H), 7.08 (q, J = 1.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.85 (d,
J = 8.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.87 (s, 1H), 3.87 (s,
3H), 3.83 (s, 3H), 2.36 (s, 3H), 1.78 (d, J = 1.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 184.7, 159.7, 153.9,
145.2, 144.5, 136.5, 134.6, 130.9 (2x), 128.8 (2x), 127.7,
127.1, 126.3, 126.2, 124.6, 124.4, 122.6, 121.5, 119.6, 111.3,
78.1, 77.3, 61.2, 55.7, 21.5, 21.4; X-Ray data: compound 6q
crystallizes in the triclinic crystal system, space group P -1, a =
12.9789(10) Å , b = 12.9834(10) Å , c = 15.1869(12) Å , V =
2300.4(3) Å 3, Z = 2, dcalcd = 1.475 g/cm3, F(000) = 1064, 2θ
range 1.463~26.436o, R indices (all data) R1 = 0.0427, wR2 =
0.0858.
(E)-1-(2-Hydroxyphenyl)-3-(7-methoxy-2-
methylbenzofuran-4-yl)-2-(phenylsulfonyl)prop-2-en-1-one
(7b). Yield = 93% (208 mg); Colorless solid; mp = 125-127 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C25H21O6S 449.1059, found 449.1063;
1H NMR (400 MHz, CDCl3): δ 7.86-7.84 (m, 2H), 7.72 (dd, J
= 2.0, 8.0 Hz, 1H), 7.60-7.56 (m, 1H), 7.48-7.44 (m, 2H), 7.38
(dt, J = 1.6, 8.8 Hz, 1H), 6.91 (dt, J = 0.8, 8.0 Hz, 1H), 6.82
(dd, J = 0.4, 8.4 Hz, 1H), 6.77 (s, 1H), 6.69 (d, J = 8.4 Hz, 1H),
6.64 (d, J = 0.8 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 4.50 (d, J =
1.2 Hz, 1H), 3.89 (s, 3H), 2.51 (d, J = 0.8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 182.2, 158.9, 156.7, 145.3, 143.9,
137.4, 137.2, 134.5, 129.4 (3x), 128.91 (2x), 128.85, 126.8,
121.7, 120.4, 119.7, 118.1, 104.6, 101.6, 74.7, 72.0, 55.9, 14.1.
(2S*,3S*)-2-(3-Methoxy-2-(2-oxopropyl)phenyl)-3-
tosylchroman-4-one (5r). Yield = 94% (218 mg); Colorless
solid; mp = 146-148 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H25O6S
1
465.1372, found 465.1780; H NMR (400 MHz, CDCl3): δ
7.72-7.68 (m, 3H), 7.44 (dt, J = 1.6, 8.8 Hz, 1H), 7.23 (d, J =
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8
(6R*,6aS*,12aS*)-6-Hydroxy-3,4-dimethoxy-6a-tosyl-
5,6,6a,12a-tetrahydro-7H-benzo[c]xanthen-7-one
7.11 (d, J = 8.8 Hz, 1H), 7.02 (dd, J = 2.4, 8.8 Hz, 1H), 6.76 (s,
1H), 3.97 (s, 3H), 3.91 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 154.5, 148.9, 141.1, 130.2, 129.8, 125.2, 124.4,
116.7, 112.1, 102.8, 60.8, 56.6. 10 is known compound and the
analytical data are consistent with those in the reference 11a.
(8).
NH4OAc (31 mg, 0.4 mmol) was added to a solution of 2a
(145 mg, 0.5 mmol) and 3a (103 mg, 0.5 mmol) in MeOH (10
o
mL) at 25 C. Then, the reaction mixture was refluxed for 5 h.
The reaction was traced by TLC until the starting materials
were consumed. The reaction mixture was cooled to 25 C.
Gram-Scale Synthesis of Compound 6a. NH4OAc (185 mg,
2.4 mmol) was added to a solution of 2a (870 mg, 3.0 mmol)
o
o
Furthermore, freshly prepared OsO4 (1.0 M in THF, 3 mL) and
NMO (50% in H2O, 350 mg, 1.5 mmol) was added to the reac-
and 3a (620 mg, 3.0 mmol) in MeOH (60 mL) at 25 C. Then,
9
the reaction mixture was refluxed for 5 h. The reaction was
traced by TLC until the starting materials were consumed. The
o
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tion mixture at 25 C. And, the reaction mixture was stirred at
o
o
25 C for 15 h. The reaction mixture was concentrated and
reaction mixture was cooled to 25 C. Furthermore, PdCl2 (54
extracted with EtOAc (3 x 60 mL). The combined organic
layers were washed with brine (2 x 10 mL), dried (MgSO4),
filtered and evaporated to afford crude product mixture under
reduced pressure. The remaining mixture was separated by
mg, 10 mol%) and CuCl2 (600 mg, 4.5 mmol) were added to
the reaction mixture. Then, molecular oxygen was bubbled
into the mixture for 2 h, and stirring occurred at 25 oC for 15 h.
The reaction mixture was concentrated and extracted with
EtOAc (4 x 80 mL). The combined organic layers were
washed with brine (2 x 10 mL), dried (MgSO4), filtered and
evaporated to afford crude product mixture under reduced
pressure. The remaining mixture was separated by column
chromatography (silica gel, hexanes/EtOAc = 30/1~10/1 as
eluent) affording 6a (1.04 g, 73%).
column chromatography (silica gel, hexanes/EtOAc
=
30/1~10/1 as eluent) affording 8. Yield = 82% (197 mg); Col-
o
orless solid; mp > 250 C (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H25O7S
1
481.1321, found 481.1332; H NMR (400 MHz, CDCl3): δ
7.68 (d, J = 8.4 Hz, 2H), 7.53 (dd, J = 1.6, 7.6 Hz, 1H), 7.33
(dt, J = 1.6, 8.4 Hz, 1H), 7.26 (dd, J = 0.8, 8.8 Hz, 1H), 7.14 (d,
J = 8.4 Hz, 2H), 6.81 (dd, J = 0.8, 8.4 Hz, 1H), 6.79 (dt, J =
0.8, 8.0 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.56 (s, 1H), 5.24
(dd, J = 2.4, 3.6 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.08 (dd, J
= 2.4, 18.4 Hz, 1H), 2.91 (dd, J = 3.6, 18.4 Hz, 1H), 2.32 (s,
3H), 1.80 (br s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
184.6, 158.4, 152.2, 146.3, 145.8, 136.8, 132.9, 130.5 (2x),
129.1, 129.0 (2x), 126.8, 124.9, 122.1, 121.6, 121.3, 118.8,
111.4, 74.6, 74.3, 67.5, 60.0, 55.6, 29.4, 21.5.
DFT calculation. The B3LYP-D3 method was employed for
the present DFT calculations. The transition metals Cu and Pd
were described by LANL2DZ basis sets with effective core
potentials, whereas the remaining elements were described by
6-31+G* basis sets. Geometry optimizations and vibrational
frequency calculations were carried under solution phase de-
scribed by the SMD solvation model (solvent = methanol).
The thermal correction to Gibbs free energy with zero-point
vibrational energies was made at standard conditions of 1 atm
and 298.15 K. The setting of ultrafine grids was adopted for
numerical integrations. All the calculations were achieved by
using the Gaussian 09 program.21
2-Phenylchromen-4-one (9)17 and 7,8-dimethoxynaphthalen-
2-ol (10).11a NH4OAc (31 mg, 0.4 mmol) was added to a solu-
tion of 2p (120 mg, 0.5 mmol) and 3a (103 mg, 0.5 mmol) in
o
MeOH (10 mL) at 25 C. Then, the reaction mixture was re-
fluxed for 5 h. The reaction was traced by TLC until the start-
ing materials were consumed. The reaction mixture was cooled
to 25 oC. Furthermore, PdCl2 (9 mg, 10 mol%) and CuCl2 (100
mg, 1.5 mmol) was added to the reaction mixture. Then, mo-
lecular oxygen was bubbled into the mixture for 2 h, and stir-
ring occurred at 25 oC for 15 h. The reaction mixture was con-
centrated and extracted with EtOAc (3 x 60 mL). The com-
bined organic layers were washed with brine (2 x 10 mL),
dried (MgSO4), filtered and evaporated to afford crude product
mixture under reduced pressure. The remaining mixture was
separated by column chromatography (silica gel, hex-
anes/EtOAc = 30/1~10/1 as eluent) affording 9 and 10.
ASSOCIATED CONTENT
Supporting Information
Scanned photocopies of NMR spectral data for all compounds,
DFT results and optimized coordinates, and X-ray analysis data of
6b, 6d-1, 6e, 6i, 5p, 6q, 5s and 7a. This information is available
free of charge via the Internet at http: //pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: mychang@kmu.edu.tw
*Email: hychen@kmu.edu.tw
ORCID
For 9: Yield = 82% (91 mg); Colorless solid; mp = 94-95 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C15H11O2 223.0759, found 223.0765;
1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J = 1.6, 8.0 Hz, 1H),
8.02-7.86 (m, 2H), 7.72 (dt, J = 1.6, 8.4 Hz, 1H), 7.60 (dd, J =
1.6, 8.4 Hz, 1H), 7.56-7.48 (m, 3H), 7.45 (dt, J = 1.2, 8.0 Hz,
1H), 7.06 (d, J = 1.2 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 178.7, 164.5, 156.2, 134.4, 132.0, 131.2, 129.1 (2x),
126.4, 125.7 (2x), 125.6, 123.0, 118.1, 106.9. 9 is known com-
pound and the analytical data are consistent with those in the
reference 17. For 10: Yield = 72% (73 mg); Colorless solid;
Meng-Yang Chang: 0000-0002-1983-8570
Hsing-Yin Chen: 0000-0003-3948-8915
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors would like to thank the Ministry of Science and
Technology of the Republic of China for financial support (MOST
106-2628-M-037-001-MY3).
o
mp = 125-126 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H13O3 205.0865,
1
REFERENCES
found 205.0872; H NMR (400 MHz, CDCl3): δ 7.66 (d, J =
8.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H),
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The Journal of Organic Chemistry
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Pot
Synthesis
of
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