Construction of Sulfonyl Oxabenzo[3.3.1]bicyclic Core via Cyclocondensation of β-Ketosulfones and o-Formyl Allylbenzenes

Article abstract of DOI:10.1021/acs.joc.7b02425

NH₄OAc mediated domino Knoevenagel/Diels-Alder cyclocondensation of β-ketosulfones 1 and o-formyl allylbenzenes 2 provides sulfonyl oxabenzo[3.3.1]bicyclic core 4 in a cosolvent of toluene and HOAc (v/v = 1/1) at reflux for 3 h. The intermediate 3 contains a chalcone motif. The uses of various ammonium salts and solvent systems are investigated for facile and efficient transformation. The plausible mechanisms have been proposed and the DFT calculations have been included.

Full text of DOI:10.1021/acs.joc.7b02425

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Article
Construction of Sulfonyl Oxabenzo[3.3.1]bicyclic Core via
Cyclocondensation of #-Ketosulfones and o-Formyl Allylbenzenes
Nai-Chen Hsueh, Hsing-Yin Chen, and Meng-Yang Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02425 • Publication Date (Web): 22 Nov 2017
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Construction of Sulfonyl Oxabenzo[3.3.1]bicyclic Core via
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Cyclocondensation of β-Ketosulfones and o-Formyl Allylbenzenes
Nai-Chen Hsueh,a Hsing-Yin Chen*a and Meng-Yang Chang*a,b
aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan bDepartment of
Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
Supporting Information Placeholder
NH OAc mediated domino Knoevenagel / Diels-Alder cyclocondensation
4

Ar
Ar
O
Z
O
NH OAc
4
Z
O
O
H O
+
+
2
S
S
O
toluene / HOAc (1 / 1)
reflux, 3 h
o
R
R
Y
O
O
Y
4
1
2
ABSTRACT: NH4OAc mediated domino Knoevenagel/Diels-Alder cyclocondensation of β-ketosulfones 1 and o-formyl
allylbenzenes 2 provides sulfonyl oxabenzo[3.3.1]bicyclic core 4 in a cosolvent of toluene and HOAc (v/v =1/1) at reflux for 3 h.
The intermediate 3 contains a chalcone motif. The uses of various ammonium salts and solvent systems are investigated for facile
and efficient transformation. The plausible mechanisms have been proposed and the DFT calculations have been included.
Introduction
However, Knoevenagel condensations have been associated
with Diels-Alder cycloadditions, Michael additions, and/or ene
reactions for the preparation of highly multi-functionalized
heterocycles.6-7 Although developed synthetic protocols have
been extensively explored for diversified skeletons, most 1,3-
dicarbonyl compounds of the reported molecules were focused
on β-ketoesters, β-diketones, and β-diesters. Among the pre-
sent scaffolds derived from domino Knoevenagel condensa-
tion and the Diels-Alder cycloaddition route, a core structure
having other β-carbonyl synthons is relatively rare, especially
those with a sulfonyl substituent (Y = RSO2).8 Herein, we
describe a highly effective synthesis of the bridged benzofused
heterocyclic core system 4 bearing a rigid conformer of (E)-β-
oxyvinyl sulfone with an electronic “push-pull” characteristic
by a domino cyclocondensation route from readily available β-
ketosulfones 1 and o-formyl allylbenzenes 2, as shown in
Scheme 2.
Recently, we developed a one-pot easy-operational route for
the synthesis of diversified carbocyclic or heterocyclic
benzofused frameworks by functionalization of β-ketosulfones
(α-sulfonyl ketones, 1)1 or o-formyl allylbenzenes (o-allyl
benzaldehydes, 2) building blocks under a series of domino
benzannulation processes.2 With receiving significant results,
we wanted to investigate the possibility of the construction of
novel core systems by the combination of two scaffolds via a
single-step domino transformation. The domino reaction can
reduce human effort, avoid reagent waste, combine multiple
reactions, and save reaction time and cost.3 In accordance with
the powerful route, Knoevenagel condensation of active α-
methylene compounds (for β-ketosulfones 1) with carbonyl
compounds (for o-formyl allylbenzenes 2) in the presence of
ammonium salts has been reported.4,5 In particular, due to car-
bonyl compounds associating with an o-allyl arm such that the
resulting intermediate (E)-3 has a chalcone motif we can pro-
ceed with further intramolecular annulation to provide the
Scheme 2. Cyclocondensation Route of 4
unexpected
bridged
skeleton
4
with
the
Ar
O
4
Knoevenagel
condensation
Ar
O
Z
Z
O
oxabenzo[3.3.1]bicyclic core under single vessel conditions
via a sequential intramolecular Diels-Alder cycloaddition
(Scheme 1).
O
o
S
+
S
R
and Diels-Alder
cycloaddition
O
O
R
Y
Y
O
1
2
Results and Discussion
Scheme 1. Combination of β-Ketosulfones and o-Formyl
Allylbenzenes
The initial study commenced with the treatment of model
substrates 1a (Ar = Ph, R = Tol, 0.5 mmol) and 2a (Y = 1-HO-
3-MeO, Z1 = Z2 = H, 0.5 mmol) with stoichiometric amounts
of NH4OAc (1.0 and 2.0 equivalents) in toluene at room tem-
perature for 3 h as shown in Table 1. However, two conditions
were unsuccessful (entries 1-2). When the reaction tempera-
Ar
O
4
Ar
O
Ar
O
O
O
O
o
+
S
S
R
S
O
O
R
O
R
Y
O
Y
Y
H
H O
2
1
2
(E)-3
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ture was increased to reflux, 56 % and 42% yields of 4a were
To study the scope and limitations of this approach, 1 and 2
provided under Dean-Stark distillation conditions, respectively
(entries 3-4). With the results in hand, by controlling 1.0
equivalent of NH4OAc at reflux temperature (111 oC), elongat-
ing reaction times (3  5 and 10 h, entries 5-6) did not pro-
vide better yields. Uncyclized 3a was isolated in a range of
16%-24% yields under a boiling toluene condition. However,
when HOAc was added to the reaction mixture, the isolated
yield of 4a was increased to 90% (entry 7). The result shows
that this domino reaction proceeded well in the presence of
HOAc. Using a cosolvent of toluene and HOAc (v/v, 1/1, 10
mL), we surveyed the effect of ammonium salts in construct-
ing a bridged core structure, such as Et4NOAc, Et4NCl,
nBu4NF, NH4F, and NH4I. However, none of them obtained
higher yields of 4a than NH4OAc. Elongating the alkyl chains
(NH4OAc  Et4NOAc), the yield of 4a was decreased (68%,
entry 8). Furthermore, after adjusting the anion from acetate to
halide, no desired products were produced (entries 9-12). Next,
other reactions (dioxane and xylene) were examined; however,
the isolated yields were similar (72% and 79%) (entries 13-14).
In entries 15-16, the concentrated (4 mL) and diluted (20 mL)
solutions of toluene and HOAc produced lower yields (82%
and 70%) than entry 7 (90%). From these observations, we
conclude that NH4OAc (1.0 equiv) provides optimal condi-
were reacted with NH4OAc to afford diversified 4, as shown in
Table 2. With optimal conditions established (Table 1, entry 7),
we found that this route allowed a direct dehydration/[4+2]
annulation under mild conditions in moderate to good yields
(73%-90%). Among entries 1~20, the efficient formation of
4a-4t showed that these substituents (for 1a-1n, Ar and R; for
2a-2f, Y and Z) did not affect the yield changes. For the elec-
tronic nature of aryl substituents (Ar) of 1, not only electron-
neutral but also electron-withdrawing and electron-donating
groups were appropriate. For sulfonyl substituents (R) of 1,
both aliphatic (Me and nBu) and aromatic groups were well-
tolerated. Different oxygenated groups (Y) and olefinic groups
(Z) on 2 were also suitable to form core structures 4. For the
overall domino Knoevenagel/Diels-Alder cyclocondensation
process, we envisioned that the electronic effect played a very
important facor for affecting the construction of
oxabenzo[3.3.1]bicyclic core because a stronger electron-
donating group (Y = 3-OH and 4-MeO) could increase the
reactivity of allylbenzaldehyde skeleton such that the
intramolecular Diels-Alder cycloaddition was triggered easily.
Furthermore, the relative stereochemical structures of 4a, 4b,
4p and 4s were determined by single-crystal X-ray crystallog-
raphy.9
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tions (refluxing toluene/HOAc,
cyclocondensation.
3
h) for one-pot
Table 2. Synthesis of 4a
Table 1. Reaction Conditionsa
Ar
O
Ar
Z
O
4
NH OAc
4
Z
O
O
+
3
S
S
O
toluene / HOAc (1 / 1)
reflux, 3 h
R
R
Y
O
O
Ph
O
Ph
O
6
4
Y
Ph
O
ammonium
salts
5
O
O
O
1
2
+
S
S
OH
OH
OH
Tol
Tol
S
O
O
O
H
Tol
conditions
entry 1, Ar =, R =
2, Y =, Z =
4, (%)b
4a, 90
4b, 83
4c, 84
4d, 83
4e, 86
4f, 83
4g, 82
4h, 84
4i, 80
O
OMe
OMe
OMe
1a
2a
4a
(E)-3a
1
2
3
4
5
6
7
8
9
1a, Ph, Tol
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
1b, 4-FC6H4, Tol
1c, Tol, Tol
ammonium
salts (equiv)
temp time 4a
(oC) (h) (%)b
entry
solvent
c
1d, 4-MeOC6H4, Tol 2a, 3-HO-4-MeO, H
1
2
3
4
5
6
7
8
9
NH4OAc (1.0) toluene
NH4OAc (2.0) toluene
NH4OAc (1.0) toluene
NH4OAc (1.0) toluene
NH4OAc (1.0) toluene
NH4OAc (1.0) toluene
25
3
3
3
3
5
─
─
c
1e, 4-CF3C6H4, Tol
1f, 4-NO2C6H4, Tol
1g, 4-PhC6H4, Tol
1h, 2-naphthyl, Tol
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
25
111
111
111
56d
42d
55d
50d
90
111 10
1i, 3,4-Cl2C6H3, Tol 2a, 3-HO-4-MeO, H
NH4OAc (1.0) toluene/HOAc
Et4NOAc (1.0) toluene/HOAc
118
118
118
118
118
118
3
3
3
3
3
3
3
3
3
3
10 1j, Ph, Ph
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
2a, 3-HO-4-MeO, H
2b, 3,4-(MeO)2, H
2b, 3,4-(MeO)2, H
4j, 87
4k, 83
4l, 87
68
11 1k, Ph, 4-FC6H4
12 1l, Ph, 4-MeOC6H4
13 1m, Ph, Me
14 1n, Ph, nBu
15 1a, Ph, Tol
16 1c, Tol, Tol
17 1a, Ph, Tol
18 1a, Ph, Tol
19 1a, Ph, Tol
20 1a, Ph, Tol
c
Et4NCl (1.0)
toluene/HOAc
─
c
10 nBu4NF (1.0) toluene/HOAc
11 NH4F (1.0)
12 NH4I (1.0)
─
─
4m, 73
4n, 76
4o, 86
4p, 89
4q, 84
c
toluene/HOAc
toluene/HOAc
c
─
13 NH4OAc (1.0) dioxane/HOAc 118
72e
79f
82g
70h
14 NH4OAc (1.0) xylene/HOAc
15 NH4OAc (1.0) toluene/HOAc
16 NH4OAc (1.0) toluene/HOAc
145
118
118
2c, 3-nBuO-4-MeO, H
2d, 3-cC5H9O-4-MeO, H 4r, 88
aThe reactions were run on a 0.5 mmol scale with 1a, 2a (1.0
equiv), solvents (10 mL). bIsolated yields. cNo reaction. d3a
was isolated in a range of 16%-24% yields. e10% of 3a was
isolated. fComplex mixture was isolated (~8%). g4 mL of tolu-
ene/HOAc (v/v = 1/1). h20 mL of toluene/HOAc (v/v = 1/1).
2e, 3,4-(MeO)2, Me
2f, 3-HO, H
4s, 80
4t, 78
aThe reactions were run on a 0.5 mmol scale with 1, 2 (1.0
equiv), NH4OAc (1.0 equiv), toluene/HOAc (v/v = 8/2, 10
mL), 3 h, reflux. bIsolated yields.
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As an extension of the one-pot route, cyclocondensations of
Knoevenagel condensation of 1a with 2a. After deprotonation
of the benzylic proton on 3b by the t-butoxide ion, two iso-
mers, 5a and 5b were obtained in a ratio of 1:1 via an
intramolecular tandem deprotonation/olefin migration/Michael
addition sequence.
β-diketones 1o-1p with 2a were investigated next (Scheme 3).
Treatment of 1o (R = Ph) with 2a provided sole 4u in a 57%
yield. However, reaction of unsymmetrical 1p (R = Me) with
2a produced only one isomer 4v (62%) along with one
uncyclized 3v (10%) due to less repulsion between acetyl and
o-allylaryl groups on 3v. Another pair of 4v-1 and 3v-1 was
not detected. By the steric effect, 3v was genrated as (E)-
configuration and was cyclized to 4v becuase phenylketone
was a bulkier group than methylketone. For the phenomenon
of steric hindrance, our experimental results were also similar
to Swenson and Zhang reports.8b The related configuration
was confirmed through 1H NMR spectrum analysis. The
methyl group of 4v-1 (a α-methyl ketone signal) should
exhibit one singlet at nearly δ 2.40-2.70. However, in the
methyl group of 4v (a vinylic signal) one singlet appeared at δ
1.58. From the two positions of two methyl group signals, we
concluded that the predicted structure of 4v was reasonable.
For the β-ketoester 1q, only a 26% yield of 4w was generated
since the ester group was unstable under refluxing acidic
conditions.
Scheme 5. Synthesis of 5a-5b
Ph
O
OBu
OMe
Ph
O
H
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t-BuOK
O
O
O
+
O
S
OMe
OMe
OMe
OMe
Tol
S
toluene
O
Ph
Tol
H
O
S
O
O
OMe
Tol
1a
2b
3b
5a (30%) + 5b (28%)
Furthermore, when NaOAc was chosen as the base for a
one-pot reaction of 1m with 2a, the chalcone skeleton 3c was
isolated in a 60% yield along with two starting materials 1m
and 2a, and trace amounts of 4m (Scheme 6). The results
showed that 3c was produced as the major product in the pres-
ence of the buffer solution of the NaOAc/HOAc system. The
structure of 3c was determined by single-crystal X-ray crystal-
lography.9
Scheme 3. Synthesis of 4u, 4v, 3v and 4w
Scheme 6. Synthesis of 3c
Me
Ph
O
O
Ph
O
NH OAc
4
O
O
+
Ph
O
O
OH
OH
or
OH
Ph
O
toluene / HOAc
(1 / 1)
reflux, 3 h
O
R
Ph
O
NaOAc
R
O
+
S
OMe
OH
OH
OMe
OMe
Me
S
O
O
Me
toluene / HOAc (1 / 1)
reflux, 3 h
H
O
1o, R = Ph
1p, R = Me
1q, R = OEt
2a
4u, R = Ph (57%)
4v-1, R = Me (ND)
4w, R = OEt (26%)
OMe
OMe
4v (62%)
1m
2a
3c (60%)
more repulsion
less repulsion
O
In contrast, the domino reaction of 1a with 2h (P = Me) or
2i (P = Ph) provided the tricyclic cis-fused 6a and 6b via a
highly regioselective process in 83% and 82% yields, respec-
tively under NH4OAc mediated conditions (Scheme 7). The
structural frameworks of 6a and 6b were determined by sin-
gle-crystal X-ray crystallography.9 The results are in agree-
ment with Tietze reports.13
Me
Ph
O
O
O
OH
OMe
OH
Ph
Me
H
H
OMe
(Z)-3v-1 (not observed) (E)-3v (10%, preferred)
As shown in Scheme 4, by changing 2-allyl to 2-vinyl group,
a one-pot domino reaction was studied. Using a boiling NaOH
methanolic solution, olefin migration of 2b was furnished to
2g.10 In particular, when 1a was reacted with 2g by the above
conditions, only a 78% yield of ynone 4x-1 was generated and
the predicted oxabenzo[3.2.1]bicyclic core 4x was not pro-
duced via the NH4OAc mediated domino Knoevenagel con-
densation and dehydrosulfonylation under refluxing condi-
tions.11
Scheme 7. Synthesis of 6a-6b
P
Ph
O
P
O
H
Ph
O
P
O
Ph
NaOAc
O
+
S
O
O
Tol
S
O
Tol
S
H
toluene / HOAc
(1 / 1)
reflux, 3 h
O
O
Tol
OMe
OMe
OMe
OMe
OMe
OMe
6a, P = Me (83%)
6b, P = Ph (82%)
4y, P = Me (ND)
4z, P = Ph (ND)
1a
2h, P = Me
2i, P = Ph
Scheme 4. Synthesis of 4x-1
Density functional theory (DFT) calculations were per-
formed to provide the rationale behind the different reaction
behavior induced by the terminal substitution on the
dienophile moiety (P group). The endo- and exo-cycloaddition
of 1a with 2a (P = H), with 2h (P = Me), and with 2i (P = Ph)
starting from the corresponding benzylidene intermediates
were calculated (Figure 1). The results show that the endo-
cycloaddition product (i.e., bridged product) is thermodynami-
cally more stable than the exo-cycloaddition product (i.e.,
tricyclic fused product) for all three systems. However, from a
kinetic point of view, the reaction 1a + 2a favors endo-
cycloaddition path whereas the reactions 1a + 2h and 1a + 2i
favor exo-cycloaddition path. In other words, the observed
Ph
Me
Me
O
O
Me
Ph
O
O
O
S
NH OAc
Ph
4
O
+
OMe
OMe
OMe
OMe
OMe
OMe
S
Tol
O
Tol
toluene / HOAc
(1 / 1)
reflux, 3 h
O
1a
2g
4x-1 (78%)
4x (ND)
After changing NH4OAc to t-BuOK, no desired bridged
skeleton 4 was observed. Unexpectedly, a pair of isomers, 5a
and 5b, with a dihydronaphthalene skeleton was isolated in
30% and 28% yields, respectively via a t-BuOK promoted
reaction of 1a with 2b in refluxing toluene for 3 h (Scheme
5).12 The initial event should show that 3b was formed by
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Figure 2. The optimized geometries of the transition states and the frontier molecular orbitals of diene and dienophile moieties. The
red wave line indicates the bond at which the molecule is divided into diene and dienophile moieties.
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Figure 1. DFT calculated free energy profile. The unit is
kcal/mol.
Scheme 8. Reaction of 1m with 2j and synthesis of 4aa
Ph
O
Ph
O
O
O
NH OAc
4
O
+
S
OH
OH
Me
S
Ph
O
Me
toluene / HOAc (1 / 1)
reflux, 3 h
O
Ph
OMe
OMe
1m
2j
3d (not observed)
Me
O
Me
O
NH OAc
4
O
O
S
+
OH
OH
Ph
S
O
O
toluene / HOAc (1 / 1)
reflux, 3 h
Ph
O
OMe
OMe
1r
2a
4aa (80%)
After adjusting aldehyde group to ketone group, a one-pot
domino reaction was examined (Scheme 8). However, when
1m was treated with 2j, no condensed product 3d was detected
under similar conditions. Ever after elongating the time to 30 h,
no reactions were observed. The results show that the carbonyl
motif of ketone 2j possessed poor reactivity for 1m such that
the Knoevenagel condensation could not be triggered. For the
present optimal cyclocondensation condition, the o-allyl
benzoketone substrate was the limitation. Furthermore, after
exchanging the methyl group (R, methanesulfonyl) and the
phenyl (Ar, phenylketone) group on β-arylketo alkylsulfone
1m, 1r with the benzenesulfonyl group and the methylketone
group was examined. By the one-pot reaction of 1r and 2a,
4aa was produced in an 80% yield. From the results, we un-
derstand that β-alkylketo arenesulfone is well-applied to dom-
ino Knoevenagel/Diels-Alder cyclocondensation.
regioselectivity is a consequence of kinetic control. Molecular
orbital analysis reveals that the cycloaddition reaction is con-
ducted through the interaction between the LUMO of diene
and the HOMO of dienophile, namely the electron flow is
from dienophile to diene. The energy gap between the HOMO
of diene and the LUMO of dienophile is relatively large and,
therefore, the role of the corresponding interaction in the
cycloaddition reaction is excluded. The LUMO of diene moie-
ty and the HOMO of dienophile moiety fixed at the transition
state geometry are depicted in Figure 2. It can be seen that the
LUMO of diene always has the largest distribution on Cc atom
(36-37%). In contrast, the HOMO distribution of dienophile is
affected by the terminal substitution. Without substitution (P =
H), the terminal Ce atom possesses a larger HOMO coefficient
(50%). As a consequence, the relative orientation between
diene and dienophile at the transition state TSendo maximizes
the orbital overlap through the CcCe interaction. On the con-
trary, the introduction of electron donating groups at terminal
Ce pushes the HOMO distribution towards the Cd atom, lead-
ing to a larger HOMO coefficient on the Cd atom (44% for P =
Me and 32% for P = Ph). Under this circumstance, the optimal
orbital overlap between the LUMO of diene and the HOMO of
dienophile occurs at the transition state TSexo (CcCd interac-
tion) rather than at TSendo. These computational results suggest
that the substitution at the terminal carbon of dienophile moie-
ty (P group) is a key factor for the product distribution.
In summary, we have developed a NH4OAc promoted one-
pot route for the synthesis of sulfonyl oxabenzo[3.3.1]bicyclic
core 4 by a domino Knoevenagel condensation/Diels-Alder
cycloaddition of β-ketosulfones 1 and o-formyl allylbenzenes
2 in a cosolvent of toluene and HOAc (v/v =1/1) at reflux for 3
h in moderate to good yields. Chalcones 3 were the key inter-
mediates. The one-pot process provides a series of multi-
functionalized 4 via a cascade pathway of one C-C and two C-
C bond formations. The structures of the key products were
confirmed by X-ray crystallography. The plausible mecha-
nisms have been proposed and the density functional theory
(DFT) calculations have been included. Further investigations
regarding the synthetic application of β-ketosulfones 1 and o-
formyl allylbenzenes 2 will be conducted and published in due
course.
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The Journal of Organic Chemistry
Experimental Section
4, dcalcd = 1.378 g/cm3, F(000) = 944, 2θ range 2.103~26.408o,
R indices (all data) R1 = 0.0382, wR2 = 0.0879.
2
3
4
5
6
7
8
9
General. All reagents and solvents were obtained from
commercial sources and used without further purification.
Reactions were routinely carried out under an atmosphere of
dry nitrogen with magnetic stirring. Products in organic sol-
vents were dried with anhydrous magnesium sulfate before
concentration in vacuo. Melting points were determined with
3-(2-Allyl-3-hydroxy-4-methoxyphenyl)-1-phenyl-2-
(toluene-4-sulfonyl)propenone (3a). For Table 1, entry 3:
Yield = 16% (37 mg); Colorless gum; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C26H25O5S 449.1423, found 449.1430; H
1
NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.79-7.76 (m, 4H),
7.45-7.41 (m, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.28-7.25 (m, 2H),
6.60 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 6.02-5.92
(m, 1H), 5.73 (br s, 1H), 5.16 (dq, J = 1.6, 10.0 Hz, 1H), 5.10
(dq, J = 1.6, 17.2 Hz, 1H), 3.74 (s, 3H), 3.63 (d, J = 5.6 Hz,
2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.7,
148.2, 144.5, 143.5, 140.2, 138.8, 137.3, 135.8, 135.3, 133.9,
129.7 (4x), 128.6 (2x), 128.4 (2x), 125.5, 124.5, 122.0, 116.0,
108.1, 55.8, 30.4, 21.6.
a SMP3 melting apparatus. H and 13C NMR spectra were
1
recorded on a Varian INOVA-400 spectrometer operating at
400 and at 100 MHz, respectively. Chemical shifts (δ) are
reported in parts per million (ppm) and the coupling constants
(J) are given in Hertz. High resolution mass spectra (HRMS)
were measured with a mass spectrometer Finnigan/Thermo
Quest MAT 95XL. X-ray crystal structures were obtained
with an Enraf-Nonius FR-590 diffractometer (CAD4, Kappa
CCD).
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
11-(4-Fluorophenyl)-5-methoxy-12-(toluene-4-sulfonyl)-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4b). Yield
= 83% (193 mg); Colorless solid; mp = 176-178 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C26H24FO5S 467.1329, found 467.1332; 1H
NMR (400 MHz, CDCl3): δ 7.24 (d, J = 8.0 Hz, 1H), 7.06-
7.01 (m, 2H), 6.93-6.88 (m, 4H), 6.87-6.81 (m, 2H), 6.77 (d, J
= 8.4 Hz, 1H), 5.79 (br s, 1H), 5.09-5.06 (m, 1H), 4.41-4.40
(m, 1H), 3.90 (s, 3H), 3.18 (dd, J = 5.2, 19.2 Hz, 1H), 3.08 (d,
J = 19.2 Hz, 1H), 2.28 (s, 3H), 2.22-2.08 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 163.1 (d, J = 247.9 Hz), 160.7, 144.7,
143.4, 142.5, 139.9, 132.9, 131.8 (d, J = 8.3 Hz, 2x), 129.6 (d,
J = 3.8 Hz), 128.7 (2x), 126.7 (2x), 120.1, 119.7, 117.8, 114.3
(d, J = 21.2 Hz, 2x), 108.4, 70.8, 56.1, 32.6, 30.4, 27.7, 21.3.
Single-crystal X-Ray diagram: crystal of compound 4b was
grown by slow diffusion of EtOAc into a solution of com-
pound 4b in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group P
2/c, a = 24.9437(14) Å , b = 8.7955(5) Å , c = 11.5489(6) Å , V
= 2526.1(2) Å 3, Z = 2, dcalcd = 1.338 g/cm3, F(000) = 1060, 2θ
range 0.819~26.408o, R indices (all data) R1 = 0.0444, wR2 =
0.1185.
A representative synthetic procedure of skeleton 2 is as fol-
lows: Sodium sulfinates (RSO2Na, 6.0 mmol) was added to a
solution of substituted 2-bromoacetophenones (5.0 mmol) in a
cosolvent of 1,4-dioxane and water (20 mL, v/v = 1:1) at rt.
The reaction mixture was stirred at reflux for 6 h. The reaction
mixture was cooled to rt, concentrated, and partitioned with
CH2Cl2 (3 x 30 mL) and water (30 mL). The combined organ-
ic layers were washed with brine, dried, filtered and evapo-
rated to afford crude β-ketosulfones under reduced pressure.
Crude β-ketosulfones 2 were recrystallized from EtOAc in
nearly quantitative yields. β-Ketosulfones 2 are known com-
pounds and the analytical data are consistent with those in
previous literature.14
A representative synthetic procedure of skeleton 4 is as fol-
lows: NH4OAc (39 mg, 0.5 mmol) was added to a solution of
1 (0.5 mmol) in a cosolvent of toluene and HOAc (v/v = 1/1,
10 mL) at rt. The reaction mixture was stirred at rt for 10 min
under Dean-Stark distillation apparatus. 2 (0.5 mmol) was
added to the reaction mixture at rt. The reaction mixture was
stirred at reflux for 3 h. The reaction mixture was cooled to rt
and the solvent was concentrated. The residue was diluted
with water (10 mL) and the mixture was extracted with
CH2Cl2 (3 x 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Purification on silica
gel (hexanes/EtOAc = 8/1~4/1) afforded 4.
5-Methoxy-12-(toluene-4-sulfonyl)-11-p-tolyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4c). Yield
= 84% (194 mg); Colorless solid; mp = 152-154 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C27H27O5S 463.1579, found 463.1578; H NMR
(400 MHz, CDCl3): δ 7.24 (d, J = 8.4 Hz, 1H), 6.99-6.89 (m,
8H), 6.77 (d, J = 8.4 Hz, 1H), 5.86 (s, 1H), 5.07-5.04 (m, 1H),
4.40-4.38 (m, 1H), 3.87 (s, 3H), 3.16 (dd, J = 4.8, 19.2 Hz,
1H), 3.09 (d, J = 18.8 Hz, 1H), 2.32 (s, 3H), 2.28 (s, 3H),
2.16-2.05 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 161.9,
144.6, 143.3, 142.2, 140.0, 139.1, 133.0, 130.7, 129.3 (2x),
128.4 (2x), 127.8 (2x), 126.7 (2x), 119.9, 118.7, 117.9, 108.3,
70.5, 56.0, 32.5, 30.4, 27.6, 21.2 (2x).
5-Methoxy-11-phenyl-12-(toluene-4-sulfonyl)-10-oxa-
tricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4a). Yield =
o
90% (202 mg); Colorless solid; mp = 201-203 C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C26H25O5S 449.1423, found 449.1424; H NMR
(400 MHz, CDCl3): δ 7.30-7.24 (m, 2H), 7.17-7.13 (m, 2H),
7.05-7.03 (m, 2H), 6.88 (s, 4H), 6.78 (d, J = 8.0 Hz, 1H), 5.77
(s, 1H), 5.09-5.06 (m, 1H), 4.43-4.41 (m, 1H), 3.90 (s, 3H),
3.18 (dd, J = 5.2, 19.6 Hz, 1H) 3.10 (d, J = 19.6 Hz, 1H), 2.26
(s, 3H), 2.19-2.09 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
161.7, 144.7, 143.4, 142.3, 134.0, 133.6, 133.1, 129.6 (2x),
129.1, 128.6 (2x), 127.3 (2x), 126.8 (2x), 120.1, 119.3, 117.9,
108.4, 70.7, 56.1, 32.6, 30.4, 27.7, 21.3. Single-crystal X-Ray
diagram: crystal of compound 4a was grown by slow diffu-
sion of EtOAc into a solution of compound 4a in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the mon-
oclinic crystal system, space group P 21/n, a = 10.3973(5) Å ,
b = 11.4451(5) Å , c = 18.3533(9) Å , V = 2161.19(18) Å 3, Z =
5-Methoxy-11-(4-methoxyphenyl)-12-(toluene-4-sulfonyl)-
10-oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol
(4d).
o
Yield = 83% (198 mg); Colorless solid; mp = 158-160 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ for C27H27O6S 479.1528, found 479.1530; H
1
NMR (400 MHz, CDCl3): δ 7.25 (d, J = 8.0 Hz, 1H), 7.00 (d,
J = 8.8 Hz, 2H), 6.92-6.87 (m, 4H), 6.77 (d, J = 8.4 Hz, 1H),
6.68 (d, J = 8.8 Hz, 2H), 5.79 (s, 1H), 5.07-5.04 (m, 1H),
4.41-4.39 (m, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.17 (dd, J = 5.2,
19.2 Hz, 1H), 3.08 (d, J = 19.2 Hz, 1H), 2.26 (s, 3H), 2.17-
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The Journal of Organic Chemistry
Page 6 of 10
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2
3
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5
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7
8
2.04 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 161.7, 160.3,
144.6, 143.4, 142.2, 140.1, 133.2, 131.1 (2x), 128.5 (2x),
126.7 (2x), 125.9, 120.0, 119.0, 117.9, 112.6 (2x), 108.4, 70.6,
56.1, 55.2, 32.6, 30.5, 27.7, 21.3.
CDCl3): δ 161.6, 144.7, 143.5, 142.3, 139.9, 133.2, 133.1,
132.1, 130.8, 129.8, 128.4 (2x), 128.3, 127.5, 126.9, 126.81,
126.78 (2x), 126.3, 126.0, 120.1, 119.8, 118.0, 108.4, 70.8,
56.1, 32.7, 30.4, 27.8, 21.2.
5-Methoxy-12-(toluene-4-sulfonyl)-11-(4-
11-(3,4-Dichlorophenyl)-5-methoxy-12-(toluene-4-
trifluoromethylphenyl)-10-oxatricyclo[7.3.1.02,7]trideca-
2,4,6,11-tetraen-6-ol (4e). Yield = 86% (222 mg); Colorless
solid; mp = 203-205 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
sulfonyl)-10-oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-
ol (4i). Yield = 80% (206 mg); Colorless solid; mp = 194-196
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C26H23Cl2O5S 517.0643, found
517.0648; 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8.0 Hz,
1H), 7.23 (d, J = 8.4 Hz, 1H), 7.06 (dd, J = 2.0, 8.4 Hz, 1H),
6.96 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.83 (d, J =
2.0 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.81 (s, 1H), 5.09-5.07
(m, 1H), 4.40 (q, J = 1.6 Hz, 1H), 3.90 (s, 3H), 3.17 (dd, J =
5.2, 19.2 Hz, 1H), 3.08 (d, J = 19.2 Hz, 1H), 2.31 (s, 3H), 2.13
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
1
C27H24F3O5S 517.1297, found 517.1302; H NMR (400 MHz,
CDCl3): δ 7.40 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H),
7.18 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.90 (d, J =
8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H), 5.90 (s, 1H), 5.09 (s,
1H), 4.40 (s, 1H), 3.88 (s, 3H), 3.18 (dd, J = 5.2, 19.6 Hz, 1H),
3.11 (d, J = 19.6 Hz, 1H), 2.27 (s, 3H), 2.19-2.09 (m, 2H); 13
C
NMR (100 MHz, CDCl3): δ 159.9, 144.8, 143.5, 142.7, 139.5,
137.1, 132.5, 130.9 (q, J = 32.6 Hz), 130.0 (2x), 128.7 (2x),
126.7 (2x), 124.1 (q, J = 3.7 Hz, 2x), 123.7 (d, J = 270.7 Hz),
120.1, 119.9 (2x), 108.4, 71.0, 56.0, 32.6, 30.2, 27.5, 21.2.
(br s, 2H); 13C NMR (100 MHz, CDCl3): δ 158.9, 144.8, 143.5,
143.1, 139.5, 133.5, 133.2, 132.5, 131.6, 131.1, 129.4, 129.3,
128.8 (2x), 126.8 (2x), 120.6, 120.0, 117.7, 108.5, 71.1, 56.1,
32.6, 30.3, 27.6, 21.3.
5-Methoxy-11-(4-nitrophenyl)-12-(toluene-4-sulfonyl)-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4f). Yield
= 83% (205 mg); Colorless solid; mp = 204-206 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C26H24NO7S 494.1274, found 494.1277; 1H
NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.8 Hz, 2H), 7.27 (d,
J = 8.8 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz,
2H), 6.96 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 5.82
(br s, 1H), 5.12-5.10 (m, 1H), 4.34-4.32 (m, 1H), 3.90 (s, 3H),
3.21-3.08 (m, 2H), 2.30 (s, 3H), 2.12 (t, J = 2.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ 159.2, 148.0, 144.8, 143.5, 143.2,
140.0, 139.5, 132.2, 130.8 (2x), 129.0 (2x), 126.7 (2x), 122.4
(2x), 120.2, 120.0, 117.6, 108.5, 71.3, 56.1, 32.6, 30.5, 27.5,
21.4.
12-Benzenesulfonyl-5-methoxy-11-phenyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4j). Yield
= 87% (189 mg); Colorless solid; mp = 210-212 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C25H23O5S 435.1266, found 435.1269; H NMR
(400 MHz, CDCl3): δ 7.29-7.25 (m, 1H), 7.25 (d, J = 8.0 Hz,
2H), 7.15-6.98 (m, 8H), 6.78 (d, J = 8.4 Hz, 1H), 5.78 (s, 1H),
5.10-5.08 (m, 1H), 4.45 (q, J = 2.8 Hz, 1H), 3.91 (s, 3H), 3.19
(dd, J = 5.6, 19.2 Hz, 1H), 3.10 (d, J = 19.2 Hz, 1H), 2.22-
2.10 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 162.0, 144.7,
143.5, 142.8, 133.4, 133.1, 131.6, 129.6 (2x), 129.2, 128.0
(2x), 127.3 (2x), 126.7 (2x), 120.1, 119.1, 117.9, 108.4, 70.8,
56.1, 32.6, 30.3, 27.7.
12-(4-Fluorobenzenesulfonyl)-5-methoxy-11-phenyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4k). Yield
= 83% (188 mg); Colorless solid; mp = 181-183 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C25H22FO5S 453.1172, found 453.1174; 1H
NMR (400 MHz, CDCl3): δ 7.30-7.26 (m, 1H), 7.24 (d, J =
8.4 Hz, 1H), 7.18-7.15 (m, 2H), 7.04-7.02 (m, 2H), 6.94-6.90
(m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.74-6.69 (m, 2H), 5.82 (s,
1H), 5.11-5.09 (m, 1H), 4.45 (q, J = 3.2 Hz, 1H), 3.90 (s, 3H),
3.20 (dd, J = 5.6, 19.6 Hz, 1H), 3.10 (d, J = 19.6 Hz, 1H),
2.24-2.11 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 164.3 (d, J
= 252.4 Hz), 162.1, 144.7, 143.5, 138.8, 133.3, 133.0, 129.6
(2x), 129.4 (d, J = 9.1 Hz, 2x), 129.3, 127.4 (2x), 119.9, 119.3,
117.9, 115.0 (d, J = 22.0 Hz, 2x), 108.3, 70.8, 56.1, 32.6, 30.3,
27.7.
11-Biphenyl-4-yl-5-methoxy-12-(toluene-4-sulfonyl)-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4g). Yield
= 82% (215 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C32H29O5S 525.1736, found 525.1733; 1H
NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.0 Hz, 1H), 7.64 (s,
1H), 7.61 (d, J = 8.4 Hz, 1H), 7.51-7.42 (m, 5H), 7.29 (d, J =
8.4 Hz, 1H), 7.10 (dd, J = 1.6, 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz,
1H), 6.79 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.81 (s,
1H), 5.12 (d, J = 1.6 Hz, 1H), 4.49 (d, J = 1.6 Hz, 1H), 3.92 (s,
3H), 3.22 (dd, J = 4.8, 18.8 Hz, 1H), 3.15 (d, J = 18.8 Hz, 1H),
2.63-2.20 (m, 1H), 2.17 (s, 3H), 2.14-2.13 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 161.6, 144.7, 143.4, 142.3, 139.9, 133.2,
133.1, 132.1, 130.8, 129.8 (2x), 128.4 (2x), 128.3 (2x), 127.5,
126.9, 126.8 (3x), 126.3, 126.0, 120.1, 119.8, 117.9, 108.4,
70.8, 56.1, 32.7, 30.4, 27.8, 21.2.
5-Methoxy-12-(4-methoxybenzenesulfonyl)-11-phenyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4l). Yield
= 87% (202 mg); Colorless solid; mp = 199-201 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
5-Methoxy-11-naphthalen-2-yl-12-(toluene-4-sulfonyl)-10-
oxa-tricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol
(4h).
o
Yield = 84% (209 mg); Colorless solid; mp = 167-169 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C30H27O5S 499.1579, found 499.1577;
1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.0 Hz, 1H), 7.63
(d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.51-7.42 (m,
3H), 7.29 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 1.6, 8.4 Hz, 1H),
6.80 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 6.68 (d, J = 8.4 Hz, 2H),
5.81 (s, 1H), 5.13-5.11 (m, 1H), 4.49 (q, J = 2.8 Hz, 1H), 3.91
(s, 3H), 3.22 (dd, J = 5.2, 19.6 Hz, 1H), 3.15 (d, J = 19.2 Hz,
1H), 2.26-2.20 (m, 2H), 2.17 (s, 3H); 13C NMR (100 MHz,
1
H]+ calcd for C26H25O6S 465.1372, found 465.1372; H NMR
(400 MHz, CDCl3): δ 7.28-7.23 (m, 2H), 7.17-7.13 (m, 2H),
7.05 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.75 (d, J =
8.4 Hz, 1H), 6.53 (d, J = 8.8 Hz, 2H), 6.00 (br s, 1H), 5.04 (d,
J = 1.6 Hz, 1H), 4.41 (d, J = 1.6 Hz, 1H), 3.83 (s, 3H), 3.70 (s,
3H), 3.17 (dd, J = 5.2, 19.6 Hz, 1H), 3.08 (d, J = 19.2 Hz, 1H),
2.17-2.04 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 161.8,
161.2, 144.5, 143.3, 134.4, 133.4, 132.9, 129.4 (2x), 128.9,
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128.6 (2x), 127.1 (2x), 119.7, 119.3, 117.8, 113.0 (2x), 108.2,
= 1.371 g/cm3, F(000) = 504, 2θ range 1.772~26.373o, R indi-
2
70.4, 55.8, 55.2, 32.4, 30.2, 27.5.
ces (all data) R1 = 0.0359, wR2 = 0.0760.
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8
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12-Methanesulfonyl-5-methoxy-11-phenyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol
6-Butoxy-5-methoxy-11-phenyl-12-(toluene-4-sulfonyl)-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraene (4q). Yield =
84% (212 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M +
(4m).
o
Yield = 73% (136 mg); Colorless solid; mp = 203-205 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H21O5S 373.1110, found 373.1112;
1H NMR (400 MHz, CDCl3): δ 7.42-7.33 (m, 5H), 7.07 (d, J =
8.0 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.82 (br s, 1H), 5.15-
5.12 (m, 1H), 4.35 (q, J = 3.2 Hz, 1H), 3.88 (s, 3H), 3.24 (dd,
J = 5.2, 19.6 Hz, 1H), 3.16 (d, J = 19.2 Hz, 1H), 2.37 (s, 3H),
2.24 (dt, J = 3.2, 13.2 Hz, 1H), 2.13-2.08 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 161.5, 144.7, 143.6, 133.9, 133.2, 129.6,
129.2 (2x), 127.7 (2x), 119.0, 118.2, 117.8, 108.3, 70.7, 56.0,
45.0, 32.6, 30.3, 27.4.
1
H]+ calcd for C30H33O5S 505.2049, found 505.2047; H NMR
(400 MHz, CDCl3): δ 7.42 (d, J = 8.4 Hz, 1H), 7.29-7.25 (m,
1H), 7.17-7.13 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.87-6.81 (m,
5H), 5.06-5.04 (m, 1H), 4.41 (q, J = 1.6 Hz, 1H), 4.06-4.00 (m,
1H), 3.95-3.90 (m, 1H), 3.86 (s, 3H), 3.22 (dd, J = 5.2, 7.6 Hz,
1H), 3.15 (d, J = 19.2 Hz, 1H), 2.25 (s, 3H), 2.19-2.08 (m,
2H), 1.78-1.70 (m, 2H), 1.55-1.46 (m, 2H), 0.97 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 161.6, 151.0, 146.2,
142.2, 139.9, 133.4, 132.7, 129.5 (2x), 129.1, 128.5 (2x),
127.2 (2x), 126.7 (2x), 125.7, 124.2, 119.3, 110.3, 72.0, 70.8,
55.8, 33.2, 32.4, 30.4, 27.6, 21.2, 19.2, 13.9.
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
12-(Butane-1-sulfonyl)-5-methoxy-11-phenyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4n). Yield
= 76% (157 mg); Colorless solid; mp = 156-158 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
6-Cyclopentyloxy-5-methoxy-11-phenyl-12-(toluene-4-
sulfonyl)-10-oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraene
(4r). Yield = 88% (227 mg); Colorless solid; mp = 134-136 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C31H33O5S 517.2049, found 517.2044;
1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.4 Hz, 1H), 7.29-
7.24 (m, 1H), 7.16-7.12 (m, 2H), 7.00-6.98 (m, 2H), 6.84-6.79
(m, 5H), 5.04-5.01 (m, 1H), 4.99-4.95 (m, 1H), 4.40 (q, J =
3.2 Hz, 1H), 3.85 (s, 3H), 3.18 (dd, J = 5.2, 19.2 Hz, 1H), 3.09
(d, J = 19.2 Hz, 1H), 2.24 (s, 3H), 2.20-2.07 (m, 2H), 1.84-
1.69 (m, 6H), 1.65-1.58 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 161.6, 150.8, 144.9, 142.1, 139.9, 133.4, 132.7,
129.5 (2x), 129.0, 128.4 (2x), 127.2 (2x), 126.6 (2x), 126.1,
123.8, 119.4, 110.4, 83.5, 70.8, 55.7, 33.6, 33.0, 32.7, 30.5,
27.6, 23.62, 23.56, 21.2.
H]+ calcd for C23H27O5S 415.1579, found 415.1580; H NMR
1
(400 MHz, CDCl3): δ 7.44-7.33 (m, 5H), 7.07 (d, J = 8.4 Hz,
1H), 6.71 (d, J = 8.4 Hz, 1H), 5.79 (s, 1H), 5.15-5.12 (m, 1H),
4.31 (q, J = 3.2 Hz, 1H), 3.87 (s, 3H), 3.23 (dd, J = 5.2, 19.2
Hz, 1H), 3.16 (d, J = 19.2 Hz, 1H), 2.41-2.34 (m, 1H), 2.29-
2.20 (m, 2H), 2.13-2.09 (m, 1H), 1.29-1.19 (m, 2H), 1.11-1.02
(m, 2H), 0.66 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 161.2, 144.7, 143.5, 133.8, 133.2, 129.7, 129.4 (2x),
127.7 (2x), 119.5, 117.9, 117.1, 108.3, 70.6, 56.0, 55.4, 32.6,
30.2, 27.5, 23.9, 21.2, 13.3.
5,6-Dimethoxy-11-phenyl-12-(toluene-4-sulfonyl)-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraene (4o). Yield =
86% (199 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M +
5,6-Dimethoxy-8-methyl-11-phenyl-12-(toluene-4-sulfonyl)-
10-oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraene (4s). Yield
= 80% (190 mg); Colorless solid; mp = 147-149 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C27H27O5S 463.1579, found 463.1580; H NMR
1
(400 MHz, CDCl3): δ 7.43 (d, J = 8.4 Hz, 1H), 7.30-7.25 (m,
1H), 7.17-7.13 (m, 2H), 7.05-7.02 (m, 2H), 6.88 (s, 4H), 6.83
(d, J = 8.4 Hz, 1H), 5.07-5.04 (m, 1H), 4.40 (q, J = 3.2 Hz,
1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.22 (dd, J = 5.2, 19.6 Hz, 1H),
1
H]+ calcd for C28H29O5S 477.1736, found 477.1741; H NMR
(400 MHz, CDCl3): δ 7.30 (d, J = 8.4 Hz, 1H), 7.29-7.25 (m,
1H), 7.17-7.13 (m, 2H), 7.04-7.99 (m, 4H), 6.94-6.91 (m, 2H),
6.83 (d, J = 8.4 Hz, 1H), 4.57 (dd, J = 2.0, 3.6 Hz, 1H), 4.37
(br s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.41 (q, J = 7.2 Hz, 1H),
2.40 (ddd, J = 0.8, 3.6, 12.8 Hz, 1H), 2.29 (s, 3H), 1.99-1.94
(m, 1H), 1.26 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 161.6, 151.3, 147.9, 142.4, 140.1, 133.7, 131.2,
131.0, 129.4 (2x), 129.2, 128.7 (2x), 127.3 (2x), 126.8 (2x),
124.4, 119.5, 110.8, 77.8, 60.7, 55.7, 37.4, 31.0, 24.0, 21.4,
19.4. Single-crystal X-Ray diagram: crystal of compound 4s
was grown by slow diffusion of EtOAc into a solution of
compound 4s in CH2Cl2 to yield colorless prisms. The com-
pound crystallizes in the monoclinic crystal system, space
group P 21/n, a = 12.0995(7) Å , b = 11.0442(6) Å , c =
18.1654(10) Å , V = 2385.7(2) Å 3, Z = 4, dcalcd = 1.327 g/cm3,
F(000) = 1008, 2θ range 1.874~26.413o, R indices (all data)
R1 = 0.0503, wR2 = 0.1051.
3.13 (d, J = 19.6 Hz, 1H), 2.26 (s, 3H), 2.18-2.07 (m, 2H); 13
C
NMR (100 MHz, CDCl3): δ 161.6, 150.9, 146.9, 142.3, 139.9,
133.5, 132.7, 129.5 (2x), 129.1, 128.6 (2x), 127.2 (2x), 126.7
(2x), 125.6, 124.5, 119.2, 110.3, 70.8, 59.8, 55.7, 32.9, 30.4,
27.6, 21.2.
5,6-Dimethoxy-12-(toluene-4-sulfonyl)-11-p-tolyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraene (4p). Yield =
o
89% (212 mg); Colorless solid; mp = 179-181 C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C28H29O5S 477.1736, found 477.1735; H NMR
1
(400 MHz, CDCl3): δ 7.41 (d, J = 8.4 Hz, 1H), 6.99-6.88 (m,
8H), 6.82 (d, J = 8.4 Hz, 1H), 5.05-5.03 (m, 1H), 4.37-4.35 (m,
1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.20 (dd, J = 5.2, 19.2 Hz, 1H),
3.12 (d, J = 19.2 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.15-2.05
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 162.0, 150.9, 146.9,
142.3, 140.1, 139.3, 132.8, 130.7, 129.4 (2x), 128.6 (2x),
127.9 (2x), 126.8 (2x), 125.7, 124.5, 118.8, 110.3, 70.7, 59.9,
55.8, 33.0, 30.5, 29.69, 21.33 (2x). Single-crystal X-Ray dia-
gram: crystal of compound 4p was grown by slow diffusion of
EtOAc into a solution of compound 4p in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group P 21, a = 11.0102(3) Å , b =
9.1251(2) Å , c = 11.4970(3) Å , V = 1154.80(5) Å 3, Z = 2, dcalcd
11-Phenyl-12-(toluene-4-sulfonyl)-10-oxa-
tricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol (4t). Yield =
o
78% (163 mg); Colorless solid; mp = 157-158 C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C25H23O4S 419.1317, found 419.1315; H NMR
(400 MHz, CDCl3): δ 7.32-7.26 (m, 3H), 7.17-7.13 (m, 2H),
7.07 (d, J = 8.0 Hz, 1H), 7.04-7.02 (m, 2H), 6.90-6.85 (m, 3H),
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7
8
6.87 (br s, 1H), 6.66 (dd, J = 0.8, 8.0 Hz, 1H), 5.10-5.08 (m,
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H19O3 307.1334, found 307.1335;
1H NMR (400 MHz, CDCl3): δ 8.06-8.03 (m, 2H), 7.90 (d, J =
8.4 Hz, 1H), 7.61-7.57 (m, 1H), 7.52-7.48 (m, 2H), 7.01 (s,
1H), 6.80 (d, J = 1.6 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 3.88 (s,
3H), 3.85 (s, 3H), 2.17 (d, J = 1.6 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 192.4, 154.7, 151.0, 141.7, 139.8, 138.5,
136.8, 133.1, 129.5, 128.7 (2x), 128.6 (2x), 127.4, 122.9,
120.3, 108.1, 61.4, 55.9, 13.1.
1H), 4.47 (dd, J = 3.2, 4.8 Hz, 1H), 3.14 (dd, J = 5.6, 19.2 Hz,
1H), 3.05 (d, J = 19.2 Hz, 1H), 2.26 (s, 3H), 2.19-2.11 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 162.2, 154.0, 142.4,
141.1, 139.8, 133.5, 129.6 (2x), 129.2, 128.7 (2x), 127.3 (2x),
126.83, 126.80 (2x), 121.5, 119.0, 118.4, 113.2, 71.0, 32.7,
30.8, 27.5, 21.3.
(6-Hydroxy-5-methoxy-11-phenyl-10-
9
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-12-
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
yl)phenylmethanone (4u). Yield = 57% (113 mg); Purple gum;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H23O4 399.1596,
found 399.1562; 1H NMR (400 MHz, CDCl3): δ 7.18-7.15 (m,
2H), 7.10-6.90 (m, 8H), 6.66 (d, J = 8.0 Hz, 1H), 6.53 (d, J =
8.4 Hz, 1H), 5.85 (br s, 1H), 5.24-5.22 (m, 1H), 4.38 (dd, J =
1.2, 4.4 Hz, 1H), 3.78 (s, 3H), 3.39 (dd, J = 5.6, 19.2 Hz, 1H),
3.29 (d, J = 19.2 Hz, 1H), 2.25 (dt, J = 3.2, 12.8 Hz, 1H), 2.11
(dt, J = 2.0, 12.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
198.6, 158.9, 144.3, 143.4, 140.0, 135.4, 134.6, 130.8, 129.4
(2x), 129.1, 128.8 (2x), 127.4 (2x), 127.3 (2x), 118.2, 117.7,
116.9, 108.3, 70.2, 55.9, 32.5, 32.3, 26.9.
12-Benzenesulfonyl-5-methoxy-11-methyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-6-ol
(4aa).
o
Yield = 80% (149 mg); Colorless solid; mp = 204-205 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H21O5S 373.1110, found 373.1112;
1H NMR (400 MHz, CDCl3): δ 7.59-7.56 (m, 2H), 7.47-7.43
(m, 1H), 7.38-7.33 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.65 (d,
J = 8.0 Hz, 1H), 5.56 (br s, 1H), 4.97-4.94 (m, 1H), 4.15 (br s,
1H), 3.82 (s, 3H), 3.11-2.99 (m, 2H), 2.03 (s, 3H), 1.99-1.93
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 162.3, 144.6, 143.6,
143.4, 132.9, 132.0, 128.6 (2x), 126.2 (2x), 119.4, 117.7,
114.9, 108.2, 70.2, 56.0, 32.3, 30.3, 27.5, 19.0.
(6-Hydroxy-5-methoxy-11-methyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraen-12-
yl)phenylmethanone (4v). Yield = 62% (104 mg); Colorless
gum; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H21O4
2-(5,6-Dimethoxy-1,2-dihydronaphthalen-1-yl)-1-phenyl-2-
(toluene-4-sulfonyl)ethanone (5a). and 2-(5,6-Dimethoxy-1,2-
dihydronaphthalen-1-yl)-1-phenyl-2-(toluene-4-
1
337.1440, found 337.1442; H NMR (400 MHz, CDCl3): δ
sulfonyl)ethanone (5b). t-BuOK (225 mg, 2.0 mmol) was add-
ed to a solution of 1a (137 mg, 0.5 mmol) in toluene (10 mL)
at rt. The reaction mixture was stirred at rt for 10 min. 2b (103
mg, 0.5 mmol) was added to the reaction mixture at rt. The
reaction mixture was stirred at reflux for 3 h. The reaction
mixture was cooled to rt and the solvent was concentrated.
The residue was diluted with water (10 mL) and the mixture
was extracted with CH2Cl2 (3 x 20 mL). The combined organ-
ic layers were washed with brine, dried, filtered and evapo-
rated to afford crude product under reduced pressure. Purifica-
tion on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 5a and
5b. For 5a: Yield = 30% (69 mg); Colorless gum; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C27H27O5S 463.1579,
7.45-7.31 (m, 5H), 6.62 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.4
Hz, 1H), 5.76 (br s, 1H), 5.03-5.00 (m, 1H), 4.16 (d, J = 1.6
Hz, 1H), 3.81 (s, 3H), 3.13 (d, J = 3.6 Hz, 2H), 2.12 (dt, J =
3.6, 12.8 Hz, 1H), 2.02 (dt, J = 1.6, 12.8 Hz, 1H), 1.58 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 197.8, 160.1, 144.2, 143.5,
141.6, 134.9, 131.3, 128.30 (2x), 128.27 (2x), 118.1, 117.9,
116.4, 108.4, 69.8, 56.0, 32.4, 31.3, 26.8, 20.8.
2-(2-Allyl-3-hydroxy-4-methoxybenzylidene)-1-
phenylbutane-1,3-dione (3v). Yield = 10% (17 mg); Colorless
gum; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H21O4
1
337.1440, found 337.1446; H NMR (400 MHz, CDCl3): δ
8.03 (s, 1H), 7.84-7.81 (m, 2H), 7.50-7.45 (m, 1H), 7.36-7.32
(m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H),
6.03-5.93 (m, 1H), 5.74 (s, 1H), 5.12 (dq, J = 1.6, 10.0 Hz,
1H), 5.01 (dq, J = 1.6, 17.2 Hz, 1H), 3.77 (s, 3H), 3.60 (dt, J =
1.6, 6.0 Hz, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
198.2, 195.8, 147.9, 143.5, 139.9, 139.1, 136.2, 135.7, 133.7,
129.1 (2x), 128.6 (2x), 125.9, 125.1, 121.9, 115.6, 108.3, 55.8,
30.4, 27.2.
1
found 463.1577; H NMR (400 MHz, CDCl3): δ 7.67 (d, J =
8.4 Hz, 2H), 7.32-7.28 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.15
(d, J = 8.4 Hz, 2H), 7.12 (d, J = 7.2 Hz, 2H), 6.97 (dd, J = 3.2,
9.6 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H),
6.24-6.20 (m, 1H), 5.46 (d, J = 10.4 Hz, 1H), 3.65 (s, 3H),
3.62 (s, 3H), 3.33-3.27 (m, 1H), 2.54-2.42 (m, 2H), 2.34 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 194.1, 152.0, 144.9,
144.8, 137.5, 135.4, 132.9, 129.6 (2x), 129.4 (2x), 127.9 (2x),
127.6 (2x), 127.5, 127.4, 125.4, 125.2, 121.9, 110.5, 69.0,
61.0, 55.6, 37.7, 26.3, 21.5. For 5b: Yield = 28% (65 mg);
Colorless gum; HRMS (ESI, M++1) calcd for C27H27O5S
6-Hydroxy-5-methoxy-11-phenyl-10-
oxatricyclo[7.3.1.02,7]trideca-2,4,6,11-tetraene-12-carboxylic
acid ethyl ester (4w). Yield = 26% (48 mg); Colorless gum;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H23O5 367.1546,
found 367.1548; 1H NMR (400 MHz, CDCl3): δ 7.34-7.29 (m,
5H), 6.94 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 5.82 (s,
1H), 5.14-5.12 (m, 1H), 4.18-4.16 (m, 1H), 4.01-43.95 (m,
1H), 3.93-3.86 (m, 1H), 3.85 (s, 3H), 3.26 (dd, J = 5.6, 19.2
Hz, 1H), 3.15 (d, J = 19.6 Hz, 1H), 2.19-2.13 (m, 1H), 2.04-
2.00 (m, 1H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 167.6, 161.6, 144.3, 143.3, 137.1, 134.9, 128.6,
128.3 (2x), 127.4 (2x), 118.34, 118.31, 108.2, 108.1, 70.2,
59.6, 55.9, 32.4, 30.4, 26.8, 13.5.
1
463.1579, found 463.1573; H NMR (400 MHz, CDCl3): δ
7.61 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.47-7.43
(m, 1H), 7.28-7.25 (m, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.15 (d,
J = 8.0 Hz, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 9.6 Hz,
1H), 5.71-5.66 (m, 1H), 5.29 (d, J = 6.0 Hz, 1H), 4.09-4.06 (m,
1H), 3.86 (s, 3H), 3.55 (s, 3H), 2.44-2.42 (m, 2H), 2.32 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 193.4, 152.3, 144.5,
144.5, 137.3, 136.1, 133.5, 129.3 (2x), 129.2 (2x), 128.32 (2x),
128.25 (2x), 127.33, 127.27, 126.8, 124.9, 122.4, 110.9, 72.6,
60.9, 55.8, 37.2, 26.0, 21.5.
3-(3,4-Dimethoxy-2-propenylphenyl)-1-phenylpropynone
3-(2-Allyl-3-hydroxy-4-methoxyphenyl)-2-methanesulfonyl-
1-phenylpropenone (3c). NaOAc (82 mg, 1.0 mmol) was add-
(4x-1). Yield = 78% (119 mg); Colorless solid; mp = 97-99 oC
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The Journal of Organic Chemistry
ed to a solution of 1m (99 mg, 0.5 mmol) in toluene (10 mL)
10.0839(5) Å , V = 2719.9(2) Å 3, Z = 4, dcalcd = 1.371 g/cm3,
2
3
4
5
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8
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at rt. The reaction mixture was stirred at rt for 10 min. 2a (96
mg, 0.5 mmol) was added to the reaction mixture at rt. The
reaction mixture was stirred at reflux for 3 h. The reaction
mixture was cooled to rt and the solvent was concentrated.
The residue was diluted with water (10 mL) and the mixture
was extracted with CH2Cl2 (3 x 20 mL). The combined organ-
ic layers were washed with brine, dried, filtered and evapo-
rated to afford crude product under reduced pressure. Purifica-
tion on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 3c.
F(000) = 1176, 2θ range 1.397~26.722o, R indices (all data)
R1 = 0.0446, wR2 = 0.0895.
6,7-Dimethoxy-1,3-diphenyl-4-(toluene-4-sulfonyl)-
1,4a,9,9a-tetrahydro-2-oxafluorene (6b). Yield = 82% (221
mg); Colorless solid; mp = 186-188 C (recrystallized from
o
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C33H31O5S 539.1892, found 539.1895; 1H NMR (400 MHz,
CDCl3): δ 7.64 (s, 1H), 7.39-7.23 (m, 6H), 7.20 (d, J = 8.4 Hz,
2H), 7.16-7.12 (m, 4H), 6.98 (d, J = 8.8 Hz, 2H), 6.78 (s, 1H),
4.68 (d, J = 6.0 Hz, 1H), 4.61 (d, J = 10.0 Hz, 1H), 4.00 (s,
3H), 3.89 (s, 3H), 3.10 (dd, J = 6.4, 15.6 Hz, 1H), 2.83-2.78
(m, 1H), 2.56 (d, J = 15.6 Hz, 1H), 2.33 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 164.0, 148.54, 148.48, 142.6, 140.0,
138.3, 137.4, 133.5, 131.3, 129.4 (2x), 129.1, 128.71 (2x),
128.67, 128.5 (2x), 127.8 (2x), 127.3 (2x), 127.0 (2x), 117.5,
109.8, 108.1, 79.4, 56.1, 56.0, 43.5, 42.2, 33.9, 21.4. Single-
crystal X-Ray diagram: crystal of compound 6b was grown by
slow diffusion of EtOAc into a solution of compound 6b in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the monoclinic crystal system, space group C 2/c, a =
21.8205(14) Å , b = 11.6934(6) Å , c = 22.0291(15) Å , V =
5596.1(6) Å 3, Z = 8, dcalcd = 1.279 g/cm3, F(000) = 2272, 2θ
range 1.857~26.365o, R indices (all data) R1 = 0.0455, wR2 =
0.1083.
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o
Yield = 60% (112 mg); Colorless solid; mp = 156-158 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H21O5S 373.1110, found 373.1112;
1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.81 (dd, J = 1.2,
8.4 Hz, 2H), 7.43 (dt, J = 1.2, 8.4 Hz, 1H), 7.28 (t, J = 8.0 Hz,
2H), 6.66 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.99-
5.89 (m, 1H), 5.80 (br s, 1H), 5.13 (dd, J = 1.6, 10.0 Hz, 1H),
5.06 (dd, J = 1.6, 16.8 Hz, 1H), 3.74 (s, 3H), 3.59 (d, J = 6.0
Hz, 2H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.6,
148.4, 143.6, 141.3, 137.4, 135.4, 135.1, 134.1, 129.7 (2x),
128.5 (2x), 125.5, 124.1, 122.1, 116.1, 108.1, 55.8, 43.6, 30.3.
Single-crystal X-Ray diagram: crystal of compound 3c was
grown by slow diffusion of EtOAc into a solution of com-
pound 3c in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group C
2/c, a = 10.3098(6) Å , b = 19.1132(9) Å , c = 19.3897(10) Å ,
V = 3769.6(3) Å 3, Z = 8, dcalcd= 1.312 g/cm3, F(000) = 1568,
2θ range 2.129~26.381o, R indices (all data) R1 = 0.0446,
wR2 = 0.0885.
DFT calculation: Geometry optimizations and frequency
calculations were carried out by using B3LYP hybrid func-
tional15 in combination with 6-31+G(d) basis set. Empirical
dispersion corrections were included in the calculations with
Grimme’s D3 method.16 The optimized geometries have been
confirmed to be local minima (all positive vibrational frequen-
cies) or transition states (one imaginary vibrational frequency).
Free energy corrections were performed at 1 atm and 384.15 K.
All calculations were accomplished by Gaussian 09 program.17
A representative synthetic procedure of skeleton 6 is as fol-
lows: NH4OAc (39 mg, 0.5 mmol) was added to a solution of
1a (137 mg, 0.5 mmol) in co-solvent of toluene and HOAc
(v/v = 1/1, 10 mL) at rt. The reaction mixture was stirred at rt
for 10 min under Dean-Stark distillation apparatus. 2m-2n
(0.5 mmol) was added to the reaction mixture at rt. The reac-
tion mixture was stirred at reflux for 3 h. The reaction mixture
was cooled to rt and the solvent was concentrated. The residue
was diluted with water (10 mL) and the mixture was extracted
with CH2Cl2 (3 x 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Purification on silica
gel (hexanes/EtOAc = 8/1~4/1) afforded 6.
ASSOCIATED CONTENT
Supporting Information
Scanned photocopies of NMR spectral data for all compounds,
DFT theoretical calculations data and X-ray analysis data of 3c,
4a, 4b, 4p, 4s, 6a, and 6b. This information is available free of
charge via the Internet at http: //pubs.acs.org.
6,7-Dimethoxy-1-methyl-3-phenyl-4-(toluene-4-sulfonyl)-
AUTHOR INFORMATION
1,4a,9,9a-tetrahydro-2-oxafluorene (6a). Yield = 83% (198
o
mg); Colorless solid; mp = 210-212 C (recrystallized from
Corresponding Author
*Email: hychen@kmu.edu.tw, mychang@kmu.edu.tw
ORCID
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C28H29O5S 477.1736, found 477.1737; 1H NMR (400 MHz,
CDCl3): δ 7.56 (s, 1H), 7.30-7.25 (m, 1H), 7.18 (d, J = 8.4 Hz,
2H), 7.17-7.13 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.97 (d, J =
8.0 Hz, 2H), 6.77 (s, 1H), 4.53 (d, J = 6.0 Hz, 1H), 3.96 (s,
3H), 3.87 (s, 3H), 3.86-3.78 (m, 1H), 3.23 (dd, J = 6.8, 15.6
Hz, 1H), 2.73 (dd, J = 2.0, 15.6 Hz, 1H), 2.44-2.38 (m, 1H),
2.31 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 163.2, 148.5, 148.4, 142.5, 140.2, 137.2, 133.9,
131.5, 129.5 (2x), 129.2, 128.7 (2x), 127.4 (2x), 126.9 (2x),
117.1, 109.8, 107.9, 73.3, 56.1, 56.0, 43.4, 42.7, 34.5, 21.4,
19.0. Single-crystal X-Ray diagram: crystal of compound 6a
was grown by slow diffusion of EtOAc into a solution of
compound 6a in CH2Cl2 to yield colorless prisms. The com-
pound crystallizes in the monoclinic crystal system, space
group P 21/n, a = 9.2620(5) Å , b = 29.1519(15) Å , c =
Meng-Yang Chang: 0000-0002-1983-8570
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).
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