CuBr2-Mediated One-Pot Synthesis of Sulfonyl 9-Fluorenylidenes

Article abstract of DOI:10.1021/acs.joc.0c00035

In this article, a high-yield method for the synthesis of sulfonyl 9-fluorenylidenes is described, which consists of a one-pot straightforward three-step synthetic route, including (i) CuBr₂-mediated α-bromination of o-arylacetophenone, (ii) sequential nucleophilic substitution of the resulting α-bromo o-arylacetophenone with sodium sulfinate (RSO₂Na), and (iii) the CuBr₂-mediated intramolecular Friedel-Crafts cyclizative dehydration. A plausible mechanism is proposed and discussed. This protocol provides a highly effective regio- and stereoselective annulation via the formation of one carbon-carbon (C-C) bond and one carbon-sulfur (C-S) bond.

Full text of DOI:10.1021/acs.joc.0c00035

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Article
CuBr2-Mediated One-Pot Synthesis of Sulfonyl 9-Fluorenylidenes
Meng-Yang Chang, Yu-Lin Tsai, and Hsing-Yin Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00035 • Publication Date (Web): 08 May 2020
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CuBr2-Mediated One-Pot Synthesis of Sulfonyl 9-Fluorenylidenes
Meng-Yang Chang,*,a-b Yu-Lin Tsaia and Hsing-Yin Chen*a
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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
Supporting Information Placeholder
O
R
S
O
Me
O
2 CuBr , RSO Na
2
2
Ar
Ar'
Ar
Ar'
EtOAc
ABSTRACT: In this article, a high-yield method for the synthesis of sulfonyl 9-fluorenylidenes is described, which consists of a
one-pot straightforward three-step synthetic route including (i) CuBr2-mediated α-bromination of o-arylacetophenone, (ii) sequen-
tial nucleophilic substitution of the resulting α-bromo o-arylacetophenone with sodium sulfinate (RSO2Na) and (iii) CuBr2-
mediated intramolecular Friedel-Crafts cyclizative dehydration. A plausible mechanism is proposed and discussed. This protocol
provides a highly effective regio- and stereoselective annulation via formation of one carbon-carbon (C-C) bond and one carbon-
sulfur (C-S) bond.
Introduction
of these advancements, some problems exist, such as multi-
step routes, complicated catalytic conditions, and lack of broad
substrate generality and prefunctionalized fragments.
The core skeleton of geminal diarylethylene is present in
many pharmacophores, including tamoxifen, bexarotene and
ratanhine.1-11 Among these 1,1-diarylethylene derivatives,
however, the tricyclic 9-fluorenylidene system (also known as
methylidenefluorene) exhibits key functionalized properties in
advanced material chemistry.12-19 Due to their potential appli-
cations, the development of a one-pot facile transition metal-
promoted synthetic route to access these motifs has attracted
significant attention, and many development attempts have
been reported. The conventional synthetic route towards sub-
stituted alkylidene or benzylidene fluorenes is based on
Knoevenagel condensation of fluorene with aliphatic and aro-
matic aldehydes.20 Recently, the palladium complex promoting
pioneering methods have been explored as a main strategy, as
shown in Scheme 1.21-28 Other routes for the formation of sub-
stituted 9-fluorenylidenes 1 have been investigated.29
Scheme 1. Synthetic Routes of 9-Fluorenylidenes 1
(Larock, ref 21)
(this work)
CN
TMS
O
+
I
TfO
(Larock, refs 22-23)
Ph
Ar
Ar'
(Gevorgyan, ref 28)
Ph
Cu(II)
Pd(II)
RSO Na
2
I
+
2
1
R
R
Pd(II)
Pd(II)
(Wudl, ref 27)
(Valdes, ref 24)
Ph
Ar
Ar'
Br
+
Br
Cu(I)
Pd(II)
N
2
2
NNHTs
9-Fluorenylidenes 1
Pd(II)/Ag(I) Pd(II)/Cu(I)
MeO
OMe
(Cheng, ref 26)
(Huang, Wen, ref 25)
Tol (HO) B Tol
Ph I I Ph
2
+
For example, Larock and coworkers reported palladium-
catalyzed (3+2) annulation of in situ formed arynes and o-
halostyrenes.21 This group also developed a Pd(OAc)2 mediat-
ed domino reaction of iodoarenes and arylacetylenes.22-23
OMe
I
N
TfO
I
+
Therefore, further investigation of efficient synthetic meth-
ods for functionalized 9-fluorenylidenes is still highly desired.
In fact, to the best of our knowledge, no vinyl sulfonyl-
conjugated substituent on the core structure of 9-
fluorenylidenes 1 has been reported to this point.30 Owing to
the specific chemoselectivity, multi-functionalized physical
properties and diversified bioactivity, the introduction of the
vinyl sulfonyl moiety to a key core skeleton has long held an
important position in synthetic organic chemistry, materials
science and pharmaceutical fields.
Paraja and Valdés demonstrated
a Pd2(dba)3 catalyzed
autotandem cross-coupling of N-tosylhydrazones and biphenyl
bromides.24 Huang and Wen explored the Pd(II)/Cu(I) mediat-
ed cascade multi-component reaction (MCR) of cyclic
iodoniums, alkynes and boronic acids.25 Cheng et al. described
a Pd(II)/Ag(I) catalyzed multiple C-H bond functionalization
of oximes and excess aryl iodides.26 The Wudl group reported
a Cu(I) catalyzed self-dimerization of 9-diazofluorenes.27
Gevorgyan et al. studied the Pd(II) catalyzed C-H activation
route to construct a methylidenefluorene framework.28 In spite
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Results and Discussion
Compared with reports on transition metal mediated reac-
tions, we initially chose commercially available copper halides
as the promoters to screen optimal reaction conditions. On the
basis of our previous copper-mediated synthetic work,32 this
study examined the formation of 8a, commencing with CuBr2
(2 equiv)-mediated treatment of model substrates 2a (Ar = Ph,
Ar’ = 3,4-(MeO)2C6H3, 1 mmol) and 6a (R = Tol, 1.1 equiv)
in EtOAc (30 mL) at 60 oC for 10 h (Table 1, entry 1). 8a was
isolated with 80% yield. In entry 2, CuCl2 provided only 15%
yield of 8a, along with the major recovery of starting material
2a (75%). With the use of CuF2, no detection of 8a was ob-
served, and the starting material 2a was recovered (entry 3).
By controlling the halide as the bromide, five metal bromides
were examined next (entries 4-8). From the results, we under-
stood that CuBr2 was a better promoter in the initial α-
halogenation step than CuCl2 or CuF2.
3
4
5
6
7
8
9
Continuing our research on the synthetic applications of β-
sulfonyl styrenes,31 we present a one-pot three-step method for
sulfonyl 9-fluorenylidenes 8 via metal halide (MXn)-mediated
α-halogenation of o-arylacetophenones 2 (derived from cross-
coupling of o-bromoacetophenones 3 with arylboronic acids 4),
sodium sulfinates (RSO2Na) 6-mediated substitution of the
formed α-bromo o-arylacetophenones 5, followed by
intramolecular Friedel-Crafts-type dehydrative annulation of
the resulting α-sulfonyl biarylketones 7 (Scheme 2).
10
11
12
13
14
15
16
17
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20
21
22
23
24
25
26
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53
54
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60
Scheme 2. Our Route to Sulfonyl 9-Fluorenylidenes 8
halogenation
substitution
annulation
O
S
O
S
R
R
X
Me
Ar
O
O
O
Ar'
7
O
O
MX
n
RSO Na 6
2
3
5
4
4
Ar'
Ar
Ar'
Ar
Ar
Ar'
5
However, no reactions occurred on ZnBr2, NiBr2, BiBr3,
InBr3 or FeBr3, respectively. To increase the yield of 8a, the
equivalency of CuBr2 was adjusted from 2.0 to 2.5, 1.0 or 0.5,
but the isolated yields could not be enhanced (entries 9-11). In
particular, by diminishing the solvent volume (30  15 or 10),
the yield of 8a was increased to 89% (entry 12) and 85% (en-
try 13), respectively. This meant that the condensed reaction
system could trigger the initial α-bromination. However, when
the reaction solvent was changed from EtOAc to CHCl3, tolu-
ene, MeNO2 or DMF, no higher yields were accomplished
(entries 14-17). No reactions were detected for CHCl3 and
toluene. MeNO2 or DMF provided a complex unknown mix-
ture. In entry 18, by elevating the reaction temperature from a
2
5
8
2a, Ar = Ph, Ar' = 3,4-(MeO) C H
2g, Ar = 4,5-(MeO) C H , Ar' = 3,4-(MeO) C H
2 6 2 2 6 3
2
6
3
2b, Ar = Ph, Ar' = 3,4,5-(MeO) C H
2h, Ar = 4,5-(MeO) C H , Ar' = 3,4,5-(MeO) C H
2 6 2 3 6 2
3
6 2
2i, Ar = 4,5-(MeO) C H , Ar' = 3-MeOC H
6 4
2c, Ar = Ph, Ar' = 3-MeOC H
2
6
2
6
4
2j, Ar = 2-thienyl, Ar' = 3,4-(MeO) C H
2d, Ar = 5-FC H , Ar' = 3,4-(MeO) C H
2
6 3
6
3
2 6 3
2k, Ar = 2-thienyl, Ar' = 3,4,5-(MeO) C H
2e, Ar = 5-FC H , Ar' = 3,4,5-(MeO) C H
3
6 2
6
3
3 6 2
2l, Ar = 2-thienyl, Ar' = 3-MeOC H
2f, Ar = 5-FC H , Ar' = 3-MeOC H
6
4
6
3
6 4
6a, R = Tol; 6b, R = Me; 6c, R = 4-FC H ; 6d, R = 4-MeOC H
6 4
6
4
Table 1. Reaction Conditionsa
O
S
O
S
Tol
Tol
Me
O
O
O
O
metal halide
4'
OMe
OMe
OMe
OMe
OMe
TolSO Na 6a
2
conditions
3'
OMe
2a
8a
7a
o
o
warming (60 C) to boiling (77 C) temperature, the yield was
decreased to 78%. Interestingly, when the reaction tempera-
ture was decreased to room temperature (25 oC), the desired 8a
was afforded in only 15% yield, along with a major 48% yield
of 7a (entry 19). Subsequently, elongated time (10 h  15 or
30 h) did improve the yields to 92% and 89%, respectively
(entries 20-21). An excellent conversion from 2a to 8a was
achieved in 15 h. From these observations, we concluded that
2 equivalents of CuBr2 provided optimal conditions (60 oC, 15
entry MXn (equiv) solvent (mL) temp (oC) time (h) %b
1
2
CuBr2 (2)
CuCl2 (2)
CuF2 (2)
ZnBr2 (2)
NiBr2 (2)
BiBr3 (2)
InBr3 (2)
FeBr3 (2)
EtOAc (30) 60
EtOAc (30) 60
EtOAc (30) 60
EtOAc (30) 60
EtOAc (30) 60
EtOAc (30) 60
EtOAc (30) 60
EtOAc (30) 60
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
15
30
80
15c
d
3
4
―
d
―
d
5
6
―
d
―
h) in the presence of TolSO2Na 6a for
a one-pot
d
7
8
―
intramolecular annulation procedure. The expeditious synthet-
ic route sets up the skeleton of sulfonyl 9-fluorenylidenes via
formation of one C-C bond and one C-S bond under mild con-
ditions.
d
―
9
CuBr2 (2.5) EtOAc (30) 60
CuBr2 (1) EtOAc (30) 60
CuBr2 (0.5) EtOAc (30) 60
74
38
12c
89
85
10
11
12
13
14
15
16
17
18
19
20
21
To study the substrate scope and limitation of this one-pot
route, 2a-2i and 6a-6d were reacted under optimal CuBr2-
mediated reaction conditions to afford diversified 8a-8x, as
shown in Scheme 3. With optimal conditions established (Ta-
ble 1, entry 20), we found that this route allowed a direct
intramolecular Friedel-Crafts annulation under easy-
operational and open-vessel conditions in moderate to excel-
lent yields. Controlling the Ar group as a phenyl group (for
2a-2c, Ar = Ph), the formation of 8a-8l showed that different
oxygenated mono-, di- or tri-substituents (3-MeO, 3,4-(MeO)2,
3,4,5-(MeO)3) on the aromatic ring (Ar’) provided yields in
the range of 70%-92% in the presence of RSO2Na 6a-6d (R =
Tol, Me, 4-FC6H4, 4-MeOC6H4). From the yield distribution,
we found that di- and tri-methoxy groups produced better
yields than the mono-methoxy group because di- and tri-
oxygenated groups provided more electron density in the Ar’
ring such that the arene ring could attack the benzylic carbonyl
group more easily to obtain better yields. For the four sulfonyl
CuBr2 (2)
CuBr2 (2)
CuBr2 (2)
CuBr2 (2)
CuBr2 (2)
CuBr2 (2)
CuBr2 (2)
CuBr2 (2)
CuBr2 (2)
CuBr2 (2)
EtOAc (15) 60
EtOAc (10) 60
CHCl3 (15) 60
Toluene (15) 60
MeNO2 (15) 60
d
―
d
―
e
―
e
DMF (15)
60
―
EtOAc (15) 77
EtOAc (15) 25
EtOAc (15) 60
EtOAc (15) 60
78
15f
92
89
aThe reactions were run on a 1.0 mmol scale with 2a, metal
b
halides (0.5-2.5 equiv), then 6a (196 mg, 1.1 equiv). Isolated
yields. c2a was recovered (entry 2, 75%; entry 11, 68%). No
d
e
f
reaction. Complex and unknown mixture. 7a (48%) was iso-
lated.
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substituents (R) of 6, aliphatic, electron-withdrawing and elec-
sired tricyclic skeleton of sulfonyl 9-fluorenylidenes 8 was
2
3
4
5
tron-donating aromatic groups were well-tolerated. With this
idea in mind, the Ar’ ring was chosen for di- and tri-methoxy
groups to investigate the following reactions.
Scheme 3. Synthesis of 8a-8xa-b
obtained, and only α-sulfonyl biarylketones 7j-7k were pro-
duced in high yields (88% and 92%) under the α-bromination
and sulfonyl substitution processes.
Scheme 5. Plausible Mechanism
6
O
R
O
S
7
8
9
Tol
Br
S
Me
Me
O
O
O
O
O
O
3
2 CuBr , RSO Na 6a-6d
2
2
CuBr
TolSO Na
2
2
4
4
Ar
Ar'
Ar
Ar'
OMe
OMe
trans-attack
OMe
OMe
OMe
OMe
EtOAc
5
5
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
2a-2i
8a-8x
2a
5a
7a
trans
O
O
S
O
S
R
R
R
S
O
O
O
Tol
O
Tol
O
MeO
MeO
MeO
MeO
MeO
OMe
OMe
O
O
H
O
S
MeO
S
S
H
OMe
Tol
O
3
O
CuBr
CuBr
2
2
H
O
OMe
8a, R = Tol (92%)
8b, R = Me (84%)
8c, R = 4-FC H (88%)
OMe
8e, R = Tol (88%)
8f, R = Me (86%)
8g, R = 4-FC H (87%)
OMe
8i, R = Tol (80%)
8j, R = Me (76%)
8k, R = 4-FC H (70%)
CuBr / H O
2
2
A1
B1
(E)-8a
CuBr
2
6
4
6
4
6 4
8d, R = 4-MeOC H (86%) 8h, R = 4-MeOC H (90%)
8l, R = 4-MeOC H (71%)
6 4
6
4
6
4
Tol
O
Tol
O
O
S
O
S
O
S
O
O
O
O
R
R
R
H
O
S
S
O
O
O
Tol
OMe
OMe
OMe
S
CuBr
2
CuBr
2
H
H
O
MeO
MeO
OMe
OMe
OMe
OMe
cis
cis-attack
F
F
CuBr / H O
2
2
OMe
OMe A2
OMe
OMe
OMe (Z)-9a
3
8m, R = Tol (83%)
8n, R = Me (86%)
8o, R = Tol (85%)
8p, R = Me (86%)
8q, R = Tol (86%)
8r, R = Me (84%)
OMe B2
O
R
O
S
O
R
R
On the basis of the experimental results, a plausible mecha-
nism for the formation of 8a is illustrated in Scheme 5. First,
one equivalent of CuBr2-mediated α-bromination of 2a fol-
lowed by TolSO2Na-mediated nucleophilic substitution of the
bromide in the resulting 5a yields 7a. Then, another equivalent
of CuBr2 chelates the carbonyl and sulfonyl groups on 7a,
yielding A1 and A2 via a six-membered ring intermediate.
From the intramolecular addition face of the dimethoxyphenyl
group, A1 is preferred for generation over A2 because it pos-
sesses a trans-configured orientation with less steric hindrance.
On the basis of the formed conformation of A1, the electron-
donating methoxy (3-MeO) group could trigger the para-
carbon of the phenyl group to stereoselectively attack the car-
bonyl site to produce B1 via copper-mediated intramolecular
Friedel-Crafts addition. By the anti-deprotonated removal (E2
process) of the copper-chelated hydroxyl group on B1, 8a was
provided, along with the release of CuBr2 and H2O.32 Two
new-forming bonds (green marks) on 8a could be orientated in
trans-configuration via formation of carbon-carbon bond and
carbon-sulfur bond. In the pathway of A2, however,
intramolecular 3-methoxy-promoted cis-addition faces bulkier
repulsion than A1 such that the (Z)-9a stereoisomer could not
be generated from B1. The DFT calculations were carried out
for the intermediates proposed in Scheme 5. The results
showed that the cis-A2 was about 7 kcal/mol higher than the
trans-A1, supporting the proposed mechanism (Figure S1, see
Supporting Information). However, the two stereoisomers of
product (E)-8a and (Z)-9a were almost isoenergetic with the
latter being slightly lower in energy than the former by 0.8
kcal/mol (Figure S1). This theoretical prediction implies that
although the stereoisomer (Z)-9a could not be generated by the
synthetic route, it should be produced from photoisomerization
of (E)-8a. For the formation of a fluorene skeleton, the reac-
tion mechanism not only explains the stereospecific trans-
orientation between sulfonyl and Ar’ groups but also demon-
strates 8a as the (E)-isomer. We envision that CuBr2 efficient-
ly controlled the formation of the copper-chelated intermediate
and increased the yield in generation of 8a.
S
S
O
O
O
OMe
OMe
OMe
OMe
OMe
S
S
MeO
OMe
MeO
8s, R = Tol (90%)
8t, R = Me (93%)
OMe
8u, R = Tol (79%)
8v, R = Me (80%)
OMe
8w, R = Tol (84%)
8x, R = Me (86%)
aThe reactions were run on a 1.0 mmol scale with 2a-2i, 6a-6d
(1.1 equiv), CuBr2 (450 mg, 2.0 mmol), and EtOAc (15 mL)
for 15 h at 60 oC. bIsolated yields.
On the other hand, when the Ar group was changed from an
electron-neutral phenyl group to electron-withdrawing 5-
fluorophenyl (for 2d-2e) and electron-donating 4,5-
dimethoxyphenyl groups (for 2f-2g), 8m-8t showed that the
different substituents (Ar and R) did not affect the yield
changes (83%-93%) in the presence of 6a-6b. For the elec-
tronic nature of the Ar substituent, not only the electron-
neutral groups but also the electron-withdrawing groups and
electron-donating groups, were suitable. Then, for the hetero-
cyclic 2-thienyl group (for 2h-2i), 8u-8x were isolated in 79%-
86% yields. Furthermore, the structures of 8b-8c, 8e, 8h, 8s-8t
and 8v were determined by single-crystal X-ray analysis.33
Surprisingly, all of the crystal structures showed that the
sulfonyl group was oriented to the same face of the Ar group.
From the literature, we found that polymethoxy-substituted
fluorenes with strong dependence on the optical properties
have been reported as highly reversible electrochromic materi-
als.34
Scheme 4. Synthesis of 7j-k
O
S
Tol
Me
O
O
O
2 CuBr , TolSO Na 6a
2
2
4'
Ar'
Ar'
EtOAc
2j, Ar' = Ph
2k, Ar' = 4-PhC H
7j, Ar' = Ph (88%)
7k, Ar' = 4-PhC H (92%)
6
4
6 4
With the above results in hand, the Ar’ group with non-
oxygenated phenyl groups was examined next (Scheme 4).
Controlling Ar = Ph and R = Tol, we adjusted the Ar’ group to
the phenyl or biphenyl groups (for 2j-2k). However, no de-
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7
8
Scheme 6. Synthesis of 8y-8aca-b
NaOH were investigated next (Scheme 8). Treatment of 8a
O
with 6a (4 equiv) provided solely 10a with the bis-sulfonyl
group in 70% yield in a cosolvent of dioxane and water (v/v =
2/1) via the intermolecular conjugate addition on the quater-
nary carbon center (eq 1). As shown in eq 2, by changing
TolSO2Na to NaOH, 10b was produced in 63% yield, along
with a trace mixture of E-8n and Z-9n isomers by a hydroxyl
group mediated Michael addition under similar conditions.
The structure of 10a was determined by single-crystal X-ray
analysis.33 From two 1,4-conjugated reactions, we understood
that bulkier tosyl and smaller hydroxyl nucleophiles were re-
active for introducing the β-substituent of sulfonyl
fluorenylidenes under refluxing conditions.
Tol
S
Me
O
9
Na(Hg), MeOH
Ar
Ar'
Ar
Ar'
8y-8ac
8a, 8e, 8m, 8o, 8q, 8u
Me
Me
Me
9
MeO
OMe
OMe
OMe
OMe
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
OMe
F
OMe
MeO
8y (87%)
Me
8aa (87%)
Me
8ac (90%)
Me
OMe
OMe
S
OMe
OMe
OMe
OMe
OMe
OMe
Scheme 8. Synthesis of 10a-10c and 11a
F
O
S
Tol
O
S
8z (80%)
8ab (90%)
8ad (ND)
O
S
Tol
Tol
O
aThe reactions were run on a 1.0 mmol scale with 8a, 8e, 8m,
8o, 8q and 8u, Na(Hg) (300 mg), and MeOH (15 mL) for 1 h
at 25 oC. bIsolated yields.
TolSO Na 6a
2
(4 equiv)
O
O
(eq 1)
OMe
OMe
dioxane-H O
2
reflux, 15 h
OMe
OMe
Me
8a
O
10a (70%)
Me
O
S
With these results in hand, desulfonylative reduction of
sulfonyl 9-fluorenylidene was examined, as shown in Scheme
6.35 Controlling the sulfonyl as the tosyl group, treatment of 8a,
8e, 8m, 8o and 8q with freshly prepared sodium amalgam
(Na(Hg)) provided 9-methylfluorenes 8y-8ac in a range of
80%-90% yields under the standard conditions via a tandem
1,4-reduction followed by desulfonylation reaction.36-37 In
particular, over-reduced products replaced the predicted
methylidenefluorenes. A possible reason for this could be that
the 9-carbon on a dibenzylic position could provide a more
reactive site for the one-pot domino reduction procedure. The
structures of 8y, 8aa and 8ac were determined by single-
crystal X-ray analysis.33 However, attempts to afford 8ad
failed due to Na(Hg)-mediated decomposition of the thienyl
ring on 8u.
S
HO
O
NaOH
(4 equiv)
O
(eq 2)
OMe
OMe
dioxane-H O
2
reflux, 15 h
F
OMe
F
OMe
10b (63%)
8n
Me
O
Me
HO
S
Tol
*
O
2 CuBr
2
O
*
TolSO Na 6a
2
(eq 3)
OMe
OMe
OMe
EtOAc
OMe
2l
10c (35%, 1:1)
O
Ph
Ph
S
Me
HO
*
O
2 CuBr
2
O
*
TolSO Na 6a
2
(eq 4)
OMe
OMe
OMe
OMe
EtOAc
2m
10d (not detected)
O
S
Tol
Scheme 7. Synthesis of 9a-9d and 9m-9n
Me
O
O
O
2 CuBr
O
S
2
O
S
O
R
R
R
TolSO Na 6a
2
(eq 5)
S
CHO
CHO
O
O
O
OMe
OMe
OMe
EtOAc
O
Et
I ,
2
2n
7l (not detected)
O
+
Ar
OMe
OMe
OMe
O
o
Tol
> 2540 A
Tol
S
5
S
EtOAc, 40 h
OMe
F
O
O
O
1) NaBH , MeOH/THF
8a-d, 8m-n
9a, R = Tol (75%)
9b, R = Me (68%)
9m, R = Tol (68%)
9n, R = Me (77%)
4
(eq 6)
2) BF -OEt , CH Cl
2
9c, R = 4-FC H (60%)
9d, R = 4-MeOC H (62%)
3
2
2
6
4
6
4
7j
11a (89% of two steps)
Encouraged by the above results, the formation of 9a was
CuBr2-mediated reaction of 2l (an ethyl group) with
TolSO2Na 6a was examined next. Surprisingly, no isolation of
the sulfonyl fluorenylidene skeleton was detected, and only
10c with a -hydroxy sulfone was isolated in 35% yield (eq 3).
On the basis of 1H-NMR spectra, the ratio of diastereomer 10c
was determined as an approximate ratio of 1/1 (see Supporting
Information). When changing the ethyl group (for 2l) to the
benzyl group (for 2m), treatment of 2m with 6a provided only
a complex and unidentified mixture under the abovementioned
CuBr2-mediated reaction conditions (eq 4). We believe that
bulkier methyl and phenyl groups provided steric strain, inhib-
iting the formation of the sulfonyl fluorenylidene skeleton.
Unexpectedly, when 2n containing an electron-withdrawing 4-
formyl group was reacted with the combination of CuBr2 and
TolSO2Na 6a (eq 5), the desired 7l was not detected within the
resulting unknown complex mixture. One possible reason
should be that CuBr2 activated the aldehyde group such that 6a
examined next, as shown in Scheme 7.38-39 Under photolytic
o
irradiation conditions (λ > 2540 Å , EtOAc, 25 C), iodine-
mediated olefin isomerization from (E)-8a to (Z)-9a was
achieved directly in 75% yield during 40 h in the presence of
excess amounts of 1,2-epoxybutane.40 The transformation was
monitored by a TLC plate. By the protocol, 9b-9d were
achieved successfully from 8b-8d (Ar = Ph) in 68%, 60% and
62% yields. For photolytic isomerization of 8m-8n with the
electron-withdrawing group (Ar = 5-FC6H3), 9m-9n were ob-
tained in 68% and 77% yields, respectively. The structures of
9a and 9c were determined by single-crystal X-ray analysis.33
These results showed that the photolytic irradiation could ena-
ble E/Z-isomerization of sulfonyl fluorenylidenes to proceed
well.
As an extension of one-pot annulations, the synthetic appli-
cations of 8a or 8n with excess nucleophiles TolSO2Na or
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1
The Journal of Organic Chemistry
could react with the corresponding bromide intermediates to
bromoacetophenones
3a-3f
(for
3a,
1-(2-
2
3
4
5
6
7
8
9
generate complex results. Following, 7j was chosen as the
model substrate to construct tricyclic non-oxygenated sulfonyl
fluorene 11a (eq 6). Reduction of 7j with NaBH4 provided the
-hydroxysulfone intermediate. Involvement of BF3·OEt2,
intramolecular Friedel-Crafts annulation of the resulting -
hydroxysulfone obtained 11a in 89% yield. By use of a two-
step synthetic route, a non-oxygenated sulfonyl fluorene was
also produced. Compared with the abovementioned CuBr2-
mediated route (Scheme 4), this present method exhibited
complementary function.
bromophenyl)ethanone;
fluorophenyl)ethanone;
dimethoxyphenyl)ethanone;
3b,
3c,
3d,
1-(2-bromo-4-
1-(2-bromo-4,5-
1-(3-bromothiophen-2-
yl)ethanone; 3e, 1-(2-bromophenyl)propan-1-one; 3f, 1-(2-
bromophenyl)-2-phenylethanone), (2) arylboronic acids 4a-4f
(for 4a, 3,4-dimethoxyphenylboronic acid; 4b, 3,4,5-
trimethoxyphenylboronic acid; 4c, 3-methoxyphenylboronic
acid; 4d, phenylboronic acid; 4e, 4-biphenylboronic acid; 4f,
4-formylphenylboronic acid), and (3) sodium sulfinates
RSO2Na 6a-6d (for 6a, R = Tol; 6b, R = Me; 6c, R = 4-FC6H4;
6d, R = 4-MeOC6H4).
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
Furthermore, a gram-scale synthesis of 8a was shown in
Scheme 9. When the reaction scale for CuBr2-mediated one-
pot annulation of 2a and TolSO2Na 6a increased to 3.9 mmol
(1.0 g) and 4.5 mmol (800 mg), 8a was isolated in 82% (1.25
General synthetic procedure of compounds 2a-2n is as fol-
lows: Commercial available arylboronic acids 4a-4f (5.0
mmol), Pd(OAc)2 (180 mg, 20 mol %), PPh3 (263 mg, 1.0
mmol) and Na2CO3 (420 mg, 4.0 mmol) were added stepwise
to a solution of commercial available o-bromoacetophenones
3a-3f (4.0 mmol) in EtOH (15 mL) at 25 oC. The reaction mix-
ture was stirred at reflux for 8 h (the reaction was traced by
TLC). The reaction mixture was cooled to 25 oC, concentrated,
and extracted with EtOAc (3 x 15 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 = 10/1-2/1) afforded compounds
2a-2n.
o
g) yield in EtOAc at 60 C. Although the yield (82%) was
slightly lower than that of the 1.0 mmol scale (92%), the route
could provide
fluorenylidene.
a gram-scale synthesis for sulfonyl 9-
Scheme 9. Gram-Scale Synthesis of 8a
O
S
Tol
Me
O
O
2 CuBr , TolSO Na 6a
2
2
OMe
OMe
EtOAc
OMe
2a (1.0 g, 3.9 mmol)
OMe
8a (82%, 1.25 g)
1-(3',4'-Dimethoxybiphenyl-2-yl)ethanone (2a). 2a was syn-
thesized according to general synthetic procedure from 3a
(792 mg, 4.0 mmol) and 4a (910 mg, 5.0 mmol); Yield = 78%
(800 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M + Na]+
In summary, we developed a CuBr2-mediated one-pot regio-
and stereoselective synthesis of sulfonyl 9-fluorenylidenes 8
via a straightforward three-step route, including α-bromination
of o-arylacetophenones 2, substitution of the resulting α-
bromo o-arylacetophenones 5 with RSO2Na 6 and Friedel-
Crafts-type annulation of α-sulfonyl o-arylacetophenones 7.
The substrate scope and limitations are investigated for facile
and efficient transformation via formation of one carbon-
carbon bond and one carbon-sulfur bond. Related plausible
mechanisms have been proposed. Photolytic E/Z-isomerization
and a conjugated addition have been discussed. Up to a dozen
structures of the products were confirmed by X-ray crystallog-
raphy. Further investigations regarding the copper-mediated
synthetic works will be conducted and published in due course.
1
calcd for C16H16NaO3 279.0997, found 279.0992; H NMR
(400 MHz, CDCl3): δ 7.48-7.43 (m, 2H), 7.37-7.32 (m, 2H),
6.89 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.84 (s, 1H),
3.88 (s, 3H), 3.85 (s, 3H), 1.98 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 205.2, 148.9, 148.8, 140.9, 140.0, 133.1,
130.4, 129.8, 127.5, 127.0, 121.2, 111.8, 111.2, 55.78, 55.76,
30.2.
1-(3',4',5'-Trimethoxybiphenyl-2-yl)ethanone (2b). 2b was
synthesized according to general synthetic procedure from 3a
(792 mg, 4.0 mmol) and 4b (1060 mg, 5.0 mmol); Yield =
76% (870 mg); Colorless solid; mp = 82-83 oC (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+
1
Experimental Section
calcd for C17H18NaO4 309.1103, found 309.1100; H NMR
General. All catalysts (metal salts), 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. The
heating mantle is used to provide a stable heat source. Prod-
ucts in organic solvents were dried with anhydrous magnesium
sulfate (MgSO4) before concentration in vacuo. Melting points
(400 MHz, CDCl3): δ 7.50-7.46 (m, 2H), 7.41-7.37 (m, 2H),
6.54 (s, 2H), 3.88 (s, 3H), 3.84 (s, 6H), 2.03 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 205.2, 153.3 (2x), 141.0, 140.2,
137.8, 136.2, 130.5, 129.7, 127.6, 127.5, 106.0 (2x), 60.9, 56.1
(2x), 30.4.
1-(3'-Methoxybiphenyl-2-yl)ethanone (2c). 2c was synthe-
sized according to general synthetic procedure from 3a (792
mg, 4.0 mmol) and 4c (760 mg, 5.0 mmol); Yield = 80% (724
mg); Colorless gum; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C15H14NaO4 249.0892, found 249.0888; 1H NMR (400
MHz, CDCl3): δ 7.55-7.52 (m, 1H), 7.49 (dt, J = 1.6, 7.6 Hz,
1H), 7.43-7.38 (m, 2H), 7.33 (dt, J = 0.4, 7.6 Hz, 1H), 6.95-
6.89 (m, 3H), 3.83 (s, 3H), 2.03 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 204.9, 159.7, 142.1, 140.9, 140.3, 130.6,
130.0, 129.7, 127.7, 127.5, 121.4, 114.3, 113.5, 55.2, 30.4.
1
were determined with a SMP3 melting apparatus. H and 13C
NMR spectra were recorded on a Varian INOVA-400 spec-
trometer 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 double focusing
mass spectrometer by ESI using a hybrid ion-trap. X-ray crys-
tal structures were determined with a diffractometer (CAD4,
Kappa CCD).
1-(5-Fluoro-3',4'-dimethoxybiphenyl-2-yl)ethanone (2d). 2d
was synthesized according to general synthetic procedure from
The starting reagents were obtained from commercial
sources and used without further purification, including (1) o-
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The Journal of Organic Chemistry
Page 6 of 14
1
2
3
4
5
6
7
8
3b (864 mg, 4.0 mmol) and 4a (910 mg, 5.0 mmol); Yield =
1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 5.2 Hz, 1H), 6.96
74% (811 mg); Colorless solid; mp = 84-86 oC (recrystallized
(d, J = 4.8 Hz, 1H), 6.85 (br s, 3H), 3.83 (s, 3H), 3.81 (s, 3H),
2.09 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 191.8,
148.8, 148.3, 146.3, 139.2, 131.7, 130.6, 128.4, 121.4, 112.1,
110.7, 55.6, 55.5, 28.8.
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+
1
calcd for C16H15FNaO3 297.0903, found 297.0900; H NMR
(400 MHz, CDCl3): δ 7.55-7.52 (m, 1H), 7.09-7.04 (m, 2H),
6.92 (d, J = 8.0 Hz, 1H), 6.86 (dd, J = 2.0, 8.0 Hz, 1H), 6.83 (d,
J = 2.0 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 1.98 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 203.8, 163.6 (d, J =
250.2 Hz), 149.4, 149.1, 143.1 (d, J = 8.4 Hz), 137.1 (d, J =
3.1 Hz), 132.2, 130.4 (d, J = 9.1 Hz), 121.2, 116.7 (d, J = 22.0
Hz), 114.1 (d, J = 21.3 Hz), 111.7, 111.3, 56.0, 55.9, 30.3.
1-[3-(3,4,5-Trimethoxyphenyl)thiophen-2-yl]ethanone (2i).
2i was synthesized according to general synthetic procedure
from 3d (816 mg, 4.0 mmol) and 4b (1060 mg, 5.0 mmol);
Yield = 75% (876 mg); Colorless solid; mp = 131-132 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C15H16NaO4S 315.0667, found 315.0664;
1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 5.2 Hz, 1H), 6.99
(d, J = 5.2 Hz, 1H), 6.54 (s, 2H), 3.82 (s, 3H), 3.79 (s, 6H),
2.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 191.8,
152.8 (2x), 146.3, 139.5, 137.8, 131.6, 131.5, 130.8, 106.2
(2x), 60.6, 55.9 (2x), 28.8.
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
1-(5-Fluoro-3',4',5'-trimethoxybiphenyl-2-yl)ethanone (2e).
2e was synthesized according to general synthetic procedure
from 3b (864 mg, 4.0 mmol) and 4b (1060 mg, 5.0 mmol);
o
Yield = 78% (949 mg); Colorless solid; mp = 78-79 C (re-
crystallized from hexanes and EtOAc); HHRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C17H17FNaO4 327.1009, found
1-Biphenyl-2-ylethanone (2j). 2j was synthesized according
to general synthetic procedure from 3a (792 mg, 4.0 mmol)
and 4d (610 mg, 5.0 mmol); Yield = 81% (635 mg); Colorless
oil; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H12NaO
1
327.1005; H NMR (400 MHz, CDCl3): δ 7.54-7.50 (m, 1H),
7.10-7.05 (m, 2H), 6.51 (s, 2H), 3.88 (s, 3H), 3.85 (s, 6H),
2.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.7,
163.5 (d, J = 250.9 Hz), 153.4 (2x), 143.1 (d, J = 8.3 Hz),
138.2, 137.1 (d, J = 2.2 Hz), 135.1 (d, J = 1.6 Hz), 130.3 (d, J
= 9.1 Hz), 116.6 (d, J = 22.9 Hz), 114.4 (d, J = 22.0 Hz),
105.9 (2x), 61.0, 56.2 (2x), 30.3.
1
219.0786, found 219.0780; H NMR (400 MHz, CDCl3): δ
7.56 (dd, J = 1.6, 7.6 Hz, 1H), 7.50 (dt, J = 1.6, 7.6 Hz, 1H),
7.45-7.33 (m, 7H), 2.01 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 204.7, 140.8, 140.6, 140.4, 130.6, 130.1, 128.7 (2x),
128.6 (2x), 127.77, 127.76, 127.3, 30.3.
1-(4,5,3',4'-Tetramethoxybiphenyl-2-yl)ethanone (2f). 2f
was synthesized according to general synthetic procedure from
3c (1032 mg, 4.0 mmol) and 4a (910 mg, 5.0 mmol); Yield =
80% (1.01 g); Colorless solid; mp = 150-151 oC (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+
1-[1,1';4',1'']Terphenyl-2-ylethanone (2k). 2k was synthe-
sized according to general synthetic procedure from 3a (792
mg, 4.0 mmol) and 4e (990 mg, 5.0 mmol); Yield = 80% (870
mg); Colorless solid; mp = 93-94 oC (recrystallized from hex-
anes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
1
calcd for C18H20NaO5 339.1208, found 339.1204; H NMR
1
(400 MHz, CDCl3): δ 7.15 (s, 1H), 6.91 (d, J = 8.0 Hz, 1H),
6.86 (dd, J = 2.0, 8.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.81 (s,
1H), 3.93 (s, 6H), 3.92 (s, 3H), 3.88 (s, 3H), 1.94 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 203.5, 150.8, 148.92,
148.88, 148.0, 135.1, 133.6, 132.7, 121.3, 112.7, 112.2,
111.20, 111.17, 56.06, 56.04, 55.95, 55.9, 30.3.
C20H16NaO 295.1099, found 295.1096; H NMR (400 MHz,
CDCl3): δ 7.70-7.65 (m, 4H), 7.60-7.36 (m, 9H), 2.01 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 204.9, 140.8, 140.7,
140.3, 140.1, 139.6, 130.7, 130.2, 129.3 (2x), 128.8 (2x),
127.9, 127.53, 127.47 (2x), 127.3 (2x), 127.0, 30.5.
1-(3',4'-Dimethoxybiphenyl-2-yl)propan-1-one (2l). 2l was
synthesized according to general synthetic procedure from 3e
(848 mg, 4.0 mmol) and 4a (910 mg, 5.0 mmol); Yield = 75%
(810 mg); Colorless oil; HRMS (ESI-TOF) m/z: [M + Na]+
1-(4,5,3',4',5'-Pentamethoxybiphenyl-2-yl)ethanone (2g). 2g
was synthesized according to general synthetic procedure from
3c (1032 mg, 4.0 mmol) and 4b (1060 mg, 5.0 mmol); Yield =
81% (1.12 g); Colorless solid; mp = 105-106 oC (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+
1
calcd for C17H18NaO3 293.1154, found 293.1150; H NMR
(400 MHz, CDCl3): δ 7.49-7.35 (m, 4H), 6.92 (d, J = 8.0 Hz,
1H), 6.87 (dd, J = 2.0, 8.4 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H),
3.92 (s, 3H), 3.88 (s, 3H), 2.26 (q, J = 7.2 Hz, 2H), 0.91 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 209.3, 148.9,
148.8, 141.1, 139.5, 133.2, 130.2, 129.8, 127.4, 127.1, 121.1,
111.8, 111.2, 55.9 (2x), 36.1, 8.6.
1
calcd for C19H22NaO6 369.1314, found 369.1308; H NMR
(400 MHz, CDCl3): δ 7.15 (s, 1H), 6.82 (s, 1H), 6.51 (s, 2H),
3.93 (s, 3H), 3.92 (s, 3H), 3.88 (s, 3H), 3.85 (s, 6H), 1.98 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.5, 153.6, 153.2
(2x), 150.8, 148.1, 136.6, 135.2, 132.6, 112.5, 111.1, 106.2
(2x), 61.0, 56.2, 56.1, 56.0, 55.9, 30.2. Single-crystal X-Ray
diagram: crystal of compound 2g was grown by slow diffusion
of EtOAc into a solution of compound 2g in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the triclinic
crystal system, space group P -1, a = 10.0533(5) Å , b =
10.1641(6) Å , c = 10.8552(6) Å , V = 890.53(9) Å 3, Z = 2, dcalcd
= 1.292 g/cm3, F(000) = 368, 2θ range 2.112~26.398o, R indi-
ces (all data) R1 = 0.0516, wR2 = 0.1126.
1-(3',4'-Dimethoxybiphenyl-2-yl)-2-phenylethanone (2m).
2m was synthesized according to general synthetic procedure
from 3f (1096 mg, 4.0 mmol) and 4a (910 mg, 5.0 mmol);
Yield = 70% (930 mg); Colorless oil; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C22H20NaO3 355.1310, found 355.1318;
1H NMR (400 MHz, CDCl3): δ 7.51-7.34 (m, 4H), 7.23-7.15
(m, 3H), 66.96-6.85 (m, 5H), 3.94 (s, 3H), 3.81 (s, 3H), 3.57 (s,
2H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.5, 149.1, 148.9,
140.6, 139.6, 134.1, 133.0, 130.4, 129.8, 129.4 (2x), 128.2
(2x), 127.9, 127.1, 126.6, 121.2, 112.0, 111.4, 55.9, 55.8, 49.4.
1-[3-(3,4-Dimethoxyphenyl)thiophen-2-yl]ethanone
(2h).
2h was synthesized according to general synthetic procedure
from 3d (816 mg, 4.0 mmol) and 4a (910 mg, 5.0 mmol);
Yield = 76% (797 mg); Colorless solid; mp = 110-111 oC (re-
crystallized from hexanes and EtOAc); HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C14H14NaO3S 285.0561, found 285.0558;
2'-Acetylbiphenyl-4-carbaldehyde (2n). 2n was synthesized
according to general synthetic procedure from 3a (792 mg, 4.0
mmol) and 4f (750 mg, 5.0 mmol); Yield = 58% (520 mg);
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Colorless oil; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
1H NMR (400 MHz, CDCl3): δ 7.66-7.63 (m, 4H), 7.58-7.38
2
3
1
C15H12NaO2 247.0735, found 247.0728; H NMR (400 MHz,
(m, 9H), 7.30-7.23 (m, 4H), 4.01 (s, 2H), 2.42 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 194.4, 145.0, 141.4, 140.2, 139.9,
138.9, 138.4, 135.9, 131.9, 130.1, 129.6 (2x), 129.40 (2x),
129.36, 128.9 (2x), 128.4 (2x), 127.82, 127.78 (2x), 127.7,
127.1 (2x), 66.5, 21.6.
CDCl3): δ 10.07 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.63 (dd, J =
1.6, 7.6 Hz, 1H), 7.56 (dt, J = 1.6, 7.6 Hz, 1H), 7.50 (d, J = 8.0
Hz, 2H), 7.51-7.48 (m, 1H), 7.39 (dd, J = 1.2, 7.6 Hz, 1H),
2.15 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.3,
191.7, 147.2, 140.2, 139.4, 135.5, 131.0, 130.3, 129.9 (2x),
129.5 (2x), 128.3 (2x), 30.3.
4
5
6
7
8
9
2,3-Dimethoxy-9-(toluene-4-sulfonylmethylene)-9H-
fluorene (8a). 8a was synthesized according to general syn-
thetic procedure from 2a (256 mg, 1.0 mmol) and 6a (196 mg,
1.1 mmol); Yield = 92% (361 mg); Red solid; mp = 189-190
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C23H20NaO4S 415.0980, found
General synthetic procedure of compounds 7a, 7j-7k and
8a-8x is as follows: CuBr2 (450 mg, 2.0 mmol) was added to a
solution of o-arylacetophenones 2a-n (1.0 mmol) in EtOAc
(15 mL) at 25 oC. The reaction mixture was stirred at 60 oC for
15 min. Then, RSO2Na 6a-d (1.1 mmol) was added to the
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
415.0974; H NMR (400 MHz, CDCl3): δ 8.68 (d, J = 7.6 Hz,
o
reaction mixture. The reaction mixture was stirred at 60 C for
1H), 7.95 (d, J = 8.0 Hz, 2H), 7.40 (dt, J = 1.2, 7.6 Hz, 1H),
7.35-7.31 (m, 3H), 7.21 (dt, J = 1.2, 7.6 Hz, 1H), 7.00 (s, 1H),
6.974 (s, 1H), 6.967 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.41 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 152.5, 149.1, 146.0,
144.5, 142.8, 139.0, 134.9, 133.6, 131.4, 129.9 (2x), 129.5,
127.2 (2x), 127.1 (2x), 122.2, 118.7, 104.8, 102.8, 56.2, 56.1,
21.6.
15 h (for 7a, 25 oC, 15 h). The reaction mixture was cooled to
o
25 C, neutralized with saturated NaHCO3(aq) (30 mL), and
extracted with EtOAc (3 x 15 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 = 10/1-2/1) afforded compounds
7a, 7j-7k and 8a-8x.
9-Methanesulfonylmethylene-2,3-dimethoxy-9H-fluorene
(8b). 8b was synthesized according to general synthetic proce-
dure from 2a (256 mg, 1.0 mmol) and 6b (112 mg, 1.1 mmol);
1-(3',4'-Dimethoxybiphenyl-2-yl)-2-(toluene-4-
sulfonyl)ethanone (7a). 7a was synthesized according to gen-
eral synthetic procedure from 2a (256 mg, 1.0 mmol) and 6a
(196 mg, 1.1 mmol); For Table 1, entry 19 (25 oC, 10 h); Yield
= 48% (197 mg); Colorless solid; mp = 165-167 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
o
Yield = 84% (265 mg); Red solid; mp = 82-83 C (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
Na]+ calcd for C17H16NaO4S 339.0667, found 339.0662; H
NMR (400 MHz, CDCl3): δ 8.46 (d, J = 7.6 Hz, 1H), 7.45 (dd,
J = 0.8, 7.6 Hz, 1H), 7.37 (dt, J = 0.8, 8.0 Hz, 1H), 7.23 (dt, J
= 1.2, 8.0 Hz, 1H), 7.04 (s, 1H), 7.03 (s, 1H), 6.95 (s, 1H),
3.99 (s, 3H), 3.94 (s, 3H), 3.23 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 152.8, 149.4, 147.6, 143.0, 135.0, 133.4,
131.7, 129.5, 129.1, 127.4, 121.4, 119.1, 104.8, 102.9, 56.3,
56.2, 43.4. Single-crystal X-Ray diagram: crystal of com-
pound 8b was grown by slow diffusion of EtOAc into a solu-
tion of compound 8b in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the triclinic crystal system, space
group P -1, a = 8.5546(2) Å , b = 9.0687(2) Å , c = 9.9760(2) Å ,
V = 740.46(3) Å 3, Z = 2, dcalcd = 1.419 g/cm3, F(000) = 332, 2θ
range 2.254~26.410o, R indices (all data) R1 = 0.0348, wR2 =
0.0860.
1
Na]+ calcd for C23H22NaO5S 433.1086, found 433.1079; H
NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.4 Hz, 2H), 7.52 (dd,
J = 1.2, 7.6 Hz, 1H), 7.47 (dd, J = 1.6, 7.6 Hz, 1H), 7.40 (dt, J
= 1.2, 7.6 Hz, 1H), 7.35 (dd, J = 0.8, 8.0 Hz, 1H), 7.27 (d, J =
8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.75-6.73 (m, 2H),
3.942 (s, 2H), 3.936 (s, 3H), 3.86 (s, 3H), 2.44 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 194.7, 149.5, 145.0, 140.5, 139.0,
136.0, 132.2, 131.8, 129.9, 129.6 (2x), 129.5, 129.2, 128.4
(2x), 127.4, 121.6, 111.8, 111.5, 66.4, 56.0 (2x), 21.7. Single-
crystal X-Ray diagram: crystal of compound 7a was grown by
slow diffusion of EtOAc into a solution of compound 7a in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the triclinic crystal system, space group P -1, a = 7.9278(10)
Å , b = 8.4094(10) Å , c = 15.9103(19) Å , V = 1001.5(2) Å 3, Z
9-(4-Fluorobenzenesulfonylmethylene)-2,3-dimethoxy-9H-
fluorene (8c). 8c was synthesized according to general syn-
thetic procedure from 2a (256 mg, 1.0 mmol) and 6c (200 mg,
1.1 mmol); Yield = 88% (348 mg); Red solid; mp = 171-172
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C22H17FNaO4S 419.0729,
=
2, dcalcd = = 432, 2θ range
1.361 g/cm3, F(000)
1.312~26.461o, R indices (all data) R1 = 0.0397, wR2 =
0.0951.
1-Biphenyl-2-yl-2-(toluene-4-sulfonyl)ethanone (7j). 7j was
synthesized according to general synthetic procedure from 2j
(196 mg, 1.0 mmol) and 6a (196 mg, 1.1 mmol); Yield = 88%
(308 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M + Na]+
1
found 419.0725; H NMR (400 MHz, CDCl3): δ 8.62 (d, J =
7.6 Hz, 1H), 8.09-8.05 (m, 2H), 7.39 (dd, J = 0.8, 7.6 Hz, 1H),
7.34 (dt, J = 0.8, 8.0 Hz, 1H), 7.23-7.17 (m, 3H), 6.98 (s, 1H),
6.96 (s, 1H), 6.94 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 165.6 (d, J = 254.0 Hz), 152.6,
149.2, 146.6, 142.8, 137.9 (d, J = 3.8 Hz), 134.9, 133.4, 131.5,
129.9 (d, J = 9.9 Hz, 2x), 129.7, 129.3, 127.2, 121.4, 118.8,
116.5 (d, J = 22.8 Hz, 2x), 104.9, 102.8, 56.2, 56.1. Single-
crystal X-Ray diagram: crystal of compound 8c was grown by
slow diffusion of EtOAc into a solution of compound 8c in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the triclinic crystal system, space group P -1, a = 9.0626(2)
Å , b = 9.7391(2) Å , c = 11.0422(2) Å , V = 897.30(3) Å 3, Z = 2,
1
calcd for C21H18NaO3S 373.0874, found 373.0870; H NMR
(400 MHz, CDCl3): δ 7.56-7.49 (m, 4H), 7.43-7.39 (m, 4H),
7.34 (dd, J = 0.8, 7.6 Hz, 1H), 7.27-7.25 (m, 2H), 7.21-7.19
(m, 2H), 3.91 (s, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 194.3, 145.0, 140.6, 139.6, 138.9, 135.9, 131.8,
130.0, 129.6 (2x), 129.3, 129.1 (2x), 128.9 (2x), 128.6, 128.4
(2x), 127.7, 66.4, 21.6.
1-[1,1';4',1'']Terphenyl-2-yl-2-(toluene-4-sulfonyl)ethanone
(7k). 7k was synthesized according to general synthetic proce-
dure from 2k (272 mg, 1.0 mmol) and 6a (196 mg, 1.1 mmol);
Yield = 90% (383 mg); Colorless gum; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C27H22NaO3S 449.1187, found 449.1182;
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dcalcd = 1.467 g/cm3, F(000) = 412, 2θ range 1.995~26.441o, R
indices (all data) R1 = 0.0429, wR2 = 0.1040.
δ 165.4 (d, J = 253.9 Hz), 156.8, 152.3, 145.6, 141.9, 141.7,
138.3 (d, J = 3.8 Hz), 137.6, 133.9, 131.0, 129.8 (d, J = 9.8 Hz,
2x), 129.1, 127.7, 125.3, 120.9, 119.2, 116.4 (d, J = 22.7 Hz,
2x), 99.3, 61.0, 60.2, 56.2.
2,3-Dimethoxy-9-(4-methoxybenzenesulfonylmethylene)-
9H-fluorene (8d). 8d was synthesized according to general
synthetic procedure from 2a (256 mg, 1.0 mmol) and 6d (213
mg, 1.1 mmol); Yield = 86% (351 mg); Red solid; mp = 168-
169 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C23H20NaO5S 431.0929, found
1,2,3-Trimethoxy-9-(4-methoxybenzenesulfonylmethylene)-
9H-fluorene (8h). 8h was synthesized according to general
synthetic procedure from 2b (286 mg, 1.0 mmol) and 6d (213
mg, 1.1 mmol); Yield = 90% (394 mg); Red solid; mp = 133-
134 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C24H22NaO6S 461.1035, found
9
1
431.0922; H NMR (400 MHz, CDCl3): δ 8.70 (d, J = 7.6 Hz,
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
1H), 7.99 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.33
(dt, J = 1.2, 8.4 Hz, 1H), 7.21 (dt, J = 1.2, 7.6 Hz, 1H), 7.00 (s,
1H), 6.98 (d, J = 8.8 Hz, 2H), 6.970 (s, 1H), 6.965 (s, 1H),
3.95 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 163.6, 152.4, 149.1, 145.4, 142.7, 134.8,
133.6, 133.5, 121.3, 129.9, 129.43 (2x), 129.37, 127.1, 122.6,
118.7, 114.4 (2x), 104.8, 102.7, 56.2, 56.1, 55.6.
1
461.1028; H NMR (400 MHz, CDCl3): δ 8.74 (d, J = 7.6 Hz,
1H), 7.98 (d, J = 8.8 Hz, 2H), 7.88 (s, 1H), 7.48 (dd, J = 0.4,
7.6 Hz, 1H), 7.35 (dt, J = 1.2, 7.6 Hz, 1H), 7.27 (dt, J = 1.2,
7.6 Hz, 1H), 6.99 (d, J = 9.2 Hz, 2H), 6.90 (s, 1H), 3.95 (s,
3H), 3.93 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 163.4 (2x), 156.6, 152.3, 144.5, 141.84,
141.75, 137.5, 134.1, 133.9, 130.8, 129.2 (2x), 127.7, 126.5,
121.2, 119.0, 114.3 (2x), 99.2, 61.1, 60.2, 56.2, 55.6. Single-
crystal X-Ray diagram: crystal of compound 8h was grown by
slow diffusion of EtOAc into a solution of compound 8h in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the triclinic crystal system, space group P -1, a = 12.1394(8)
Å , b = 12.8311(9) Å , c = 16.4085(12) Å , V = 2401.3(3) Å 3, Z
1,2,3-Trimethoxy-9-(toluene-4-sulfonylmethylene)-9H-
fluorene (8e). 8e was synthesized according to general syn-
thetic procedure from 2b (286 mg, 1.0 mmol) and 6a (196 mg,
1.1 mmol); Yield = 88% (371 mg); Red solid; mp = 148-149
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C24H22NaO5S 445.1086, found
1
445.1078; H NMR (400 MHz, CDCl3): δ 8.71 (d, J = 7.6 Hz,
=
4, dcalcd = = 920, 2θ range
1.213 g/cm3, F(000)
1H), 7.93 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H), 7.46 (d, J = 7.6 Hz,
1H), 7.35-7.30 (m, 3H), 7.24 (dt, J = 1.2, 7.6 Hz, 1H), 6.89 (s,
1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.83 (s, 3H), 2.40 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 156.6, 152.2, 144.9,
144.2, 141.8, 141.7, 139.2, 137.5, 134.0, 130.8, 129.7 (2x),
129.1, 127.6, 126.9 (2x), 126.0, 121.1, 119.0, 99.2, 61.0, 60.2,
56.2, 21.5. Single-crystal X-Ray diagram: crystal of com-
pound 8e was grown by slow diffusion of EtOAc into a solu-
tion of compound 8e in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the triclinic crystal system, space
group P -1, a = 9.4622(6) Å , b = 9.7507(6) Å , c = 13.1691(10)
Å , V = 1022.78(12) Å 3, Z = 2, dcalcd = 1.372 g/cm3, F(000) =
444, 2θ range 1.636~26.507o, R indices (all data) R1 = 0.0724,
wR2 = 0.1696.
1.315~26.466o, R indices (all data) R1 = 0.1030, wR2 =
0.1813.
3-Methoxy-9-(toluene-4-sulfonylmethylene)-9H-fluorene
(8i). 8i was synthesized according to general synthetic proce-
dure from 2c (226 mg, 1.0 mmol) and 6a (196 mg, 1.1 mmol);
Yield = 80% (290 mg); Red solid; mp = 161-162 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
Na]+ calcd for C22H18NaO3S 385.0874, found 385.0871; H
NMR (400 MHz, CDCl3): δ 8.72 (d, J = 8.8 Hz, 1H), 7.93 (d,
J = 8.4 Hz, 2H), 7.53 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.6 Hz,
1H), 7.37 (dt, J = 0.8, 7.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H),
7.22 (dt, J = 1.2, 7.6 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 6.99 (s,
1H), 6.82 (dd, J = 2.8, 8.8 Hz, 1H), 3.91 (s, 3H), 2.42 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 162.8, 145.2, 145.1,
144.5, 140.4, 139.0, 138.9, 131.5, 131.0, 129.9 (2x), 127.8,
127.1 (2x), 126.0, 121.4, 121.2, 119.9, 113.0, 106.0, 55.6, 21.6.
9-Methanesulfonylmethylene-1,2,3-trimethoxy-9H-fluorene
(8f). 8f was synthesized according to general synthetic proce-
dure from 2b (286 mg, 1.0 mmol) and 6b (112 mg, 1.1 mmol);
Yield = 86% (298 mg); Red gum; HRMS (ESI-TOF) m/z: [M
9-Methanesulfonylmethylene-3-methoxy-9H-fluorene (8j).
8j was synthesized according to general synthetic procedure
from 2c (226 mg, 1.0 mmol) and 6b (112 mg, 1.1 mmol);
Yield = 76% (217 mg); Red solid; mp = 171-172 oC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
1
+ Na]+ calcd for C18H18NaO5S 369.0773, found 369.0768; H
NMR (400 MHz, CDCl3): δ 8.52 (d, J = 8.0 Hz, 1H), 7.80 (s,
1H), 7.49 (dd, J = 0.4, 7.6 Hz, 1H), 7.35 (dt, J = 1.2, 7.6 Hz,
1H), 7.25 (dt, J = 1.2, 7.6 Hz, 1H), 6.90 (s, 1H), 4.03 (s, 3H),
3.95 (s, 3H), 3.85 (s, 3H), 3.19 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 156.8, 152.4, 146.2, 141.9, 141.6, 137.4,
133.8, 131.0, 128.7, 127.8, 125.0, 120.6, 119.3, 99.2, 61.0,
60.3, 56.2, 43.2.
1
Na]+ calcd for C16H14NaO3S 309.0561, found 309.0557; H
NMR (400 MHz, CDCl3): δ 8.49 (d, J = 8.8 Hz, 1H), 7.56 (d,
J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.6 Hz,
1H), 7.29 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 6.97 (d,
J = 9.2 Hz, 1H), 6.82 (dd, J = 2.4, 8.8 Hz, 1H), 3.92 (s, 3H),
3.21 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 163.0,
146.7, 145.4, 140.4, 138.5, 131.4, 131.1, 128.1, 125.7, 121.5,
120.2, 120.0, 113.1, 106.3, 55.6, 43.2.
9-(4-Fluorobenzenesulfonylmethylene)-1,2,3-trimethoxy-
9H-fluorene (8g). 8g was synthesized according to general
synthetic procedure from 2b (286 mg, 1.0 mmol) and 6c (200
mg, 1.1 mmol); Yield = 87% (371 mg); Red solid; mp = 127-
128 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C23H19FNaO5S 449.0835,
9-(4-Fluorobenzenesulfonylmethylene)-3-methoxy-9H-
fluorene (8k). 8k was synthesized according to general syn-
thetic procedure from 2c (226 mg, 1.0 mmol) and 6c (200 mg,
1.1 mmol); Yield = 70% (256 mg); Red gum; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C21H15FNaO3S 389.0624,
1
found 449.0827; H NMR (400 MHz, CDCl3): δ 8.67 (d, J =
8.0 Hz, 1H), 8.09-8.05 (m, 2H), 7.86 (s, 1H), 7.47 (dd, J = 0.4,
7.6 Hz, 1H), 7.35 (dt, J = 0.8, 7.6 Hz, 1H), 7.26 (dt, J = 1.2,
7.6 Hz, 1H), 7.23-7.19 (m, 2H), 6.90 (s, 1H), 3.95 (s, 3H),
3.94 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
1
found 389.0619; H NMR (400 MHz, CDCl3): δ 8.68 (d, J =
8.8 Hz, 1H), 8.08-8.05 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.48
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(d, J = 7.6 Hz, 1H), 7.38 (dt, J = 0.8, 7.6 Hz, 1H), 7.25-7.19
164.8 (d, J = 250.2 Hz), 156.7, 152.3, 144.7 (d, J = 9.9 Hz),
2
(m, 3H), 7.09 (d, J = 2.8 Hz, 1H), 6.96 (s, 1H), 6.81 (dd, J =
2.8, 8.8 Hz, 1H), 3.91 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 165.7 (d, J = 254.0 Hz), 163.0, 145.8, 145.3, 140.4,
138.8 (d, J = 3.8 Hz), 138.0, 131.5, 131.3, 129.9 (d, J = 9.9 Hz,
2x), 128.0, 125.8, 121.5, 120.4, 120.0, 116.6 (d, J = 22.7 Hz,
2x), 113.0, 106.2, 55.6.
144.4, 143.7, 142.3, 139.2, 136.3, 131.1 (d, J = 9.8 Hz), 130.0
(d, J = 3.0 Hz), 129.9 (2x), 127.1 (2x), 125.9 (d, J = 2.3 Hz),
122.1, 114.1 (d, J = 21.9 Hz), 106.7 (d, J = 24.2 Hz), 99.5,
61.1, 60.3, 56.3, 21.6.
3
4
5
6
7
8
9
6-Fluoro-9-methanesulfonylmethylene-1,2,3-trimethoxy-9H-
fluorene (8p). 8p was synthesized according to general syn-
thetic procedure from 2e (304 mg, 1.0 mmol) and 6b (112 mg,
1.1 mmol); Yield = 86% (313 mg); Red solid; mp = 141-142
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C18H17FNaO5S 387.0678,
3-Methoxy-9-(4-methoxybenzenesulfonylmethylene)-9H-
fluorene (8l). 8l was synthesized according to general synthet-
ic procedure from 2c (226 mg, 1.0 mmol) and 6d (213 mg, 1.1
mmol); Yield = 71% (268 mg); Red gum; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C22H18NaO4S 401.0824, found
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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
found 387.0676; H NMR (400 MHz, CDCl3): δ 8.55 (dd, J =
1
401.0817; H NMR (400 MHz, CDCl3): δ 8.74 (d, J = 8.8 Hz,
5.2, 8.4 Hz, 1H), 7.80 (s, 1H), 7.19 (dd, J = 2.8, 8.0 Hz, 1H),
6.95 (dt, J = 2.8, 8.8 Hz, 1H), 6.88 (s, 1H), 4.06 (s, 3H), 3.98
(s, 3H), 3.88 (s, 3H), 3.20 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 164.9 (d, J = 250.9 Hz), 156.9, 152.4, 145.0, 144.8,
142.3, 136.3, 131.7 (d, J = 9.9 Hz), 129.9 (d, J = 3.0 Hz),
124.7 (d, J = 2.3 Hz), 122.7, 114.3 (d, J = 22.0 Hz), 107.0 (d, J
= 23.5 Hz), 99.5, 61.1, 60.5, 56.4, 43.5.
1H), 7.98 (d, J = 9.2 Hz, 2H), 7.53 (d, J = 7.2 Hz, 1H), 7.47 (d,
J = 7.6 Hz, 1H), 7.36 (dt, J = 1.2, 7.6 Hz, 1H), 7.21 (dt, J = 1.2,
7.6 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 7.01-6.97 (m, 3H), 6.82
(dd, J = 2.4, 8.8 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 163.6, 162.8, 145.1, 144.6, 140.3,
138.9, 133.6, 131.5, 131.0, 129.4, 129.3, 127.8, 126.0, 121.6,
121.4, 119.9, 114.5 (2x), 113.0, 106.0, 55.7, 55.6.
2,3,6,7-Tetramethoxy-9-(toluene-4-sulfonylmethylene)-9H-
fluorene (8q). 8q was synthesized according to general syn-
thetic procedure from 2f (316 mg, 1.0 mmol) and 6a (196 mg,
1.1 mmol); Yield = 86% (389 mg); Red solid; mp = 206-207
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C25H24NaO6S 475.1191, found
475.1184; 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.91 (d,
J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.90 (s, 3H), 6.80 (s,
1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (s, 3H), 2.40
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 152.2, 151.9,
148.2, 147.7, 146.2, 144.5, 139.1, 137.4, 134.9, 130.3, 129.9
(2x), 126.8 (2x), 125.9, 120.0, 113.2, 105.1, 102.3, 102.1,
56.20, 56.17, 56.1, 56.0, 21.6.
6-Fluoro-2,3-dimethoxy-9-(toluene-4-sulfonylmethylene)-
9H-fluorene (8m). 8m was synthesized according to general
synthetic procedure from 2d (274 mg, 1.0 mmol) and 6a (196
mg, 1.1 mmol); Yield = 83% (340 mg); Red solid; mp = 197-
198 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C23H19FNaO4S 433.0886,
found 433.0884; 1H NMR (400 MHz, CDCl3): δ 8.68-8.64 (m,
1H), 7.93 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.07
(dd, J = 1.6, 8.0 Hz, 1H), 6.95 (s, 1H), 6.95-6.92 (m, 1H), 6.92
(s, 1H), 6.85 (dt, J = 2.0, 8.8 Hz, 1H), 3.95 (s, 3H), 3.90 (s,
3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.1
(d, J = 250.2 Hz), 152.5, 149.6, 145.7 (d, J = 9.1 Hz), 144.7,
144.6, 138.8, 133.5, 131.3 (d, J = 9.9 Hz), 130.9, 129.9 (2x),
129.4, 127.2 (2x), 121.9 (d, J = 1.5 Hz), 113.3 (d, J = 22.0 Hz),
106.5 (d, J = 23.5 Hz), 104.7, 102.9, 56.24, 56.20, 21.6.
9-Methanesulfonylmethylene-2,3,6,7-tetramethoxy-9H-
fluorene (8r). 8r was synthesized according to general synthet-
ic procedure from 2f (316 mg, 1.0 mmol) and 6b (112 mg, 1.1
o
6-Fluoro-9-methanesulfonylmethylene-2,3-dimethoxy-9H-
fluorene (8n). 8n was synthesized according to general syn-
thetic procedure from 2d (274 mg, 1.0 mmol) and 6b (112 mg,
1.1 mmol); Yield = 86% (287 mg); Red solid; mp = 241-242
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C17H15FNaO4S 357.0573,
mmol); Yield = 84% (316 mg); Red solid; mp = 242-243 C
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C19H20NaO6S 399.0878, found
399.0872; 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 6.93 (s,
1H), 6.91 (s, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 3.98 (s, 3H), 3.97
(s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 3.19 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 152.3, 152.1, 148.3, 147.9, 147.4, 137.6,
134.9, 129.9, 125.6, 119.1, 112.7, 105.0, 102.4, 102.3, 56.2
(2x), 56.11, 56.07, 43.4.
1
found 357.0570; H NMR (400 MHz, CDCl3): δ 8.47 (dd, J =
4.8, 8.4 Hz, 1H), 7.14 (dd, J = 2.4, 8.4 Hz, 1H), 7.04 (s, 1H),
7.01 (s, 1H), 6.92 (s, 1H), 6.89 (dt, J = 2.4, 8.4 Hz, 1H), 3.99
(s, 3H), 3.95 (s, 3H), 3.22 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 165.3 (d, J = 251.7 Hz), 152.8, 149.9, 146.3, 146.0
(d, J = 9.1 Hz), 133.6, 130.9 (d, J = 9.8 Hz), 130.5, 129.3,
121.0 (d, J = 1.5 Hz), 113.6 (d, J = 22.8 Hz), 107.0 (d, J =
23.5 Hz), 104.7, 103.1, 56.3 (2x), 43.5.
1,2,3,6,7-Pentamethoxy-9-(toluene-4-sulfonylmethylene)-
9H-fluorene (8s). 8s was synthesized according to general
synthetic procedure from 2g (346 mg, 1.0 mmol) and 6a (196
mg, 1.1 mmol); Yield = 90% (434 mg); Red solid; mp = 203-
204 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C26H26NaO7S 505.1297, found
505.1291; 1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 7.91 (d,
J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.94 (s,
1H), 6.77 (s, 1H), 3.98 (s, 3H), 3.954 (s, 3H), 3.947 (s, 3H),
3.93 (s, 3H), 3.82 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 156.4 (2x), 152.3, 151.6, 148.4, 145.4, 144.2,
141.0, 139.5, 137.7, 136.3, 129.8 (2x), 126.8 (2x), 124.1,
121.4, 112.8, 102.1, 98.7, 61.1, 60.3, 56.3, 56.2, 56.1, 21.6.
Single-crystal X-Ray diagram: crystal of compound 8s was
grown by slow diffusion of EtOAc into a solution of com-
pound 8s in CH2Cl2 to yield colorless prisms. The compound
6-Fluoro-1,2,3-trimethoxy-9-(toluene-4-sulfonylmethylene)-
9H-fluorene (8o). 8o was synthesized according to general
synthetic procedure from 2e (304 mg, 1.0 mmol) and 6a (196
mg, 1.1 mmol); Yield = 85% (374 mg); Red solid; mp = 170-
171 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C24H21FNaO5S 463.0991,
1
found 463.0985; H NMR (400 MHz, CDCl3): δ 8.72 (dd, J =
5.2, 8.4 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 7.34 (d,
J = 8.4 Hz, 2H), 7.15 (dd, J = 2.4, 8.4 Hz, 1H), 6.93 (dt, J =
2.8, 8.8 Hz, 1H), 6.86 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.84
(s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
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8
o
crystallizes in the monoclinic crystal system, space group P
21/n, a = 8.1007(8) Å , b = 25.249(3) Å , c = 11.9527(11) Å , V
= 2367.4(4) Å 3, Z = 4, dcalcd = 1.354 g/cm3, F(000) = 1016, 2θ
range 1.613~26.403o, R indices (all data) R1 = 0.0418, wR2 =
0.0867.
mp = 135-136 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H20NaO5S2
451.0650, found 451.0643; H NMR (400 MHz, CDCl3): δ
1
7.93 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 4.8 Hz, 1H), 7.48 (s, 1H),
7.30 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 5.2 Hz, 1H), 6.70 (s, 1H),
3.95 (s, 3H), 3.92 (s, 3H), 3.80 (s, 3H), 2.40 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 156.1, 152.4, 151.6, 144.5, 140.7,
140.5, 138.9, 136.8, 134.3, 134.1, 129.8 (2x), 127.0 (2x),
123.7, 121.2, 118.1, 100.2, 61.1, 60.4, 56.3, 21.6.
9-Methanesulfonylmethylene-1,2,3,6,7-pentamethoxy-9H-
fluorene (8t). 8t was synthesized according to general synthet-
ic procedure from 2g (346 mg, 1.0 mmol) and 6b (112 mg, 1.1
9
o
mmol); Yield = 93% (378 mg); Red solid; mp = 176-177 C
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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
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C20H22NaO7S 429.0984, found
429.0976; 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.68 (s,
1H), 6.96 (s, 1H), 6.78 (s, 1H), 4.02 (s, 3H), 3.98 (s, 3H), 3.96
(s, 3H), 3.92 (s, 3H), 3.84 (s, 3H), 3.18 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 156.6, 152.3, 151.8, 148.5, 146.3, 140.9,
137.6, 136.4, 126.5, 123.1, 120.9, 112.3, 102.3, 98.7, 61.0,
60.4, 56.3, 56.12, 56.06, 43.3. Single-crystal X-Ray diagram:
crystal of compound 8t was grown by slow diffusion of
EtOAc into a solution of compound 8t in CH2Cl2 to yield col-
orless prisms. The compound crystallizes in the monoclinic
crystal system, space group P 21/c, a = 19.3636(3) Å , b =
13.1724(2) Å , c = 14.6482(3) Å , V = 3709.69(11) Å 3, Z = 8,
dcalcd = 1.455 g/cm3, F(000) = 1712, 2θ range 1.874~26.394o,
R indices (all data) R1 = 0.0395, wR2 = 0.0921.
8-Methanesulfonylmethylene-5,6,7-trimethoxy-8H-1-
thiacyclopenta[a]indene (8x). 8x was synthesized according to
general synthetic procedure from 2i (292 mg, 1.0 mmol) and
6b (112 mg, 1.1 mmol); Yield = 86% (303 mg); Red solid; mp
= 112-114 oC (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H16NaO5S2
1
375.0337, found 375.0333; H NMR (400 MHz, CDCl3): δ
7.55 (d, J = 4.8 Hz, 1H), 7.46 (s, 1H), 7.08 (d, J = 4.8 Hz, 1H),
6.72 (s, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 3.84 (s, 3H), 3.14 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 156.3, 152.6, 151.8,
142.4, 140.5, 137.0, 134.1, 134.0, 123.1, 120.3, 118.3, 100.3,
61.1, 60.5, 56.3, 43.0.
General synthetic procedure of compounds 8y-8ac is as fol-
lows: Freshly prepared Na(Hg) (300 mg) was added to a solu-
tion of 8a, 8c, 8m, 8o, 8q (1.0 mmol) in MeOH (15 mL) at 25
oC. The reaction mixture was stirred at 25 oC for 1 h. The reac-
tion mixture was filtrated and concentrated. The crude prod-
ucts was diluted with saturated NaHCO3(aq) (10 mL), and ex-
tracted with EtOAc (3 x 15 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to af-
ford crude product under reduced pressure. Purification on
silica gel (hexanes/EtOAc = 10/1-2/1) afforded compounds
8y-8ac.
5,6-Dimethoxy-8-(toluene-4-sulfonylmethylene)-8H-1-
thiacyclopenta[a]indene (8u). 8u was synthesized according
to general synthetic procedure from 2h (262 mg, 1.0 mmol)
and 6a (196 mg, 1.1 mmol); Yield = 79% (314 mg); Red solid;
o
mp = 184-185 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H18NaO4S2
1
421.0544, found 421.0537; H NMR (400 MHz, CDCl3): δ
7.94 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 4.8 Hz, 1H), 7.33 (d, J =
8.0 Hz, 2H), 7.06 (d, J = 5.2 Hz, 1H), 6.95 (s, 1H), 6.86 (s,
1H), 6.65 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 2.42 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 152.9, 151.6, 147.5,
144.9, 141.6, 138.6, 137.5, 133.1, 132.9, 131.6, 130.0 (2x),
127.2 (2x), 118.3, 117.4, 106.6, 103.5, 56.3, 56.2, 21.7.
2,3-Dimethoxy-9-methyl-9H-fluorene (8y). 8y was synthe-
sized according to general synthetic procedure from 8a (392
mg, 1.0 mmol); Yield = 87% (209 mg); White solid; mp =
o
130-132 C (recrystallized from hexanes and EtOAc); HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C16H16NaO2 263.1048,
1
8-Methanesulfonylmethylene-5,6-dimethoxy-8H-1-
found 263.1045; H NMR (400 MHz, CDCl3): δ 7.65 (d, J =
thiacyclopenta[a]indene (8v). 8v was synthesized according to
general synthetic procedure from 2h (262 mg, 1.0 mmol) and
6b (112 mg, 1.1 mmol); Yield = 80% (258 mg); Red solid; mp
= 205-206 oC (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H14NaO4S2
7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H),
7.27 (s, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 4.00 (s, 3H),
3.97 (s, 3H), 3.86 (q, J = 7.6 Hz, 1H), 1.51 (d, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 149.0, 149.9, 148.7,
141.5, 140.8, 132.8, 126.8, 125.6, 123.7, 118.7, 107.2, 102.9,
56.09, 56.08, 42.2, 18.3. Single-crystal X-Ray diagram: crystal
of compound 8y was grown by slow diffusion of EtOAc into a
solution of compound 8y in CH2Cl2 to yield colorless prisms.
The compound crystallizes in the triclinic crystal system,
space group P -1, a = 10.592(4) Å , b = 10.873(5) Å , c =
11.134(4) Å , V = 1249.1(9) Å 3, Z = 2, dcalcd = 1.278 g/cm3,
F(000) = 512, 2θ range 1.866~26.602o, R indices (all data) R1
= 0.1193, wR2 = 0.2436.
1
345.0233, found 345.0227; H NMR (400 MHz, CDCl3): δ
7.56 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 7.02 (s, 1H),
6.86 (s, 1H), 6.69 (s, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.15 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.1, 151.8, 147.6,
143.5, 137.7 (2x), 132.7, 131.7, 118.4, 116.2, 106.6, 103.9,
56.4, 56.2, 43.2. Single-crystal X-Ray diagram: crystal of
compound 8v was grown by slow diffusion of EtOAc into a
solution of compound 8v in CH2Cl2 to yield colorless prisms.
The compound crystallizes in the triclinic crystal system,
space group P -1, a = 8.6178(7) Å , b = 9.0183(7) Å , c =
9.6399(8) Å , V = 713.24(10) Å 3, Z = 2, dcalcd = 1.501 g/cm3,
F(000) = 336, 2θ range 2.213~26.392o, R indices (all data) R1
= 0.0360, wR2 = 0.0824.
1,2,3-Trimethoxy-9-methyl-9H-fluorene (8z). 8z was syn-
thesized according to general synthetic procedure from 8c
(396 mg, 1.0 mmol); Yield = 80% (216 mg); Colorless gum;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H18NaO3
1
293.1154, found 293.1150; H NMR (400 MHz, CDCl3): δ
5,6,7-Trimethoxy-8-(toluene-4-sulfonylmethylene)-8H-1-
thiacyclopenta[a]indene (8w). 8w was synthesized according
to general synthetic procedure from 2i (292 mg, 1.0 mmol)
and 6a (196 mg, 1.1 mmol); Yield = 84% (360 mg); Red solid;
7.66 (d, J = 7.2 Hz, 1H), 7.48 (dd, J = 0.8, 7.6 Hz, 1H), 7.35
(dt, J = 1.2, 8.0 Hz, 1H), 7.29 (dt, J = 1.2, 7.6 Hz, 1H), 7.08 (s,
1H), 4.05 (q, J = 7.2 Hz, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 3.94
(s, 3H), 1.57 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
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The Journal of Organic Chemistry
CDCl3): δ 153.8, 150.8, 149.5, 141.5, 140.3, 136.3, 132.9,
a nitrogen atmosphere with a lamp (λ > 2540 Å), using a Py-
2
3
o
126.7, 126.4, 123.8, 119.2, 99.0, 61.0, 60.6, 56.2, 41.3, 17.5.
rex glass filter at 25 C for 40 h. The reaction mixture was
washed with saturated Na2S2O3(aq) (3 x 15 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 = 10/1-4/1) afforded
compounds 9a-9d and 9m-9n.
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5
6
7
8
9
6-Fluoro-2,3-dimethoxy-9-methyl-9H-fluorene (8aa). 8aa
was synthesized according to general synthetic procedure from
8m (410 mg, 1.0 mmol); Yield = 87% (225 mg); White solid;
o
mp = 129-131 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H15FNaO2
1
281.0954, found 281.0951; H NMR (400 MHz, CDCl3): δ
2,3-Dimethoxy-9-(toluene-4-sulfonylmethylene)-9H-
fluorene (9a). 9a was synthesized according to general syn-
thetic procedure from 8a (118 mg, 0.3 mmol); Yield = 75%
7.36 (dd, J = 4.8, 8.0 Hz, 1H), 7.29 (dd, J = 2.0, 8.8 Hz, 1H),
7.19 (s, 1H), 7.02 (s, 1H), 6.92 (dt, J = 2.4, 8.0 Hz, 1H), 3.98
(s, 3H), 3.96 (s, 3H), 3.80 (q, J = 7.2 Hz, 1H), 1.47 (d, J = 7.6
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 162.7 (d, J =
241.0 Hz), 149.4, 148.8, 144.3 (d, J = 2.3 Hz), 142.7 (d, J =
9.1 Hz), 142.6, 132.0 (d, J = 3.0 Hz), 124.5 (d, J = 9.1 Hz),
122.1 (d, J = 22.8 Hz), 107.1, 105.8 (d, J = 22.7 Hz), 103.0,
56.12, 56.09, 41.7, 18.3. Single-crystal X-Ray diagram: crystal
of compound 8aa was grown by slow diffusion of EtOAc into
a solution of compound 8aa in CH2Cl2 to yield colorless
prisms. The compound crystallizes in the monoclinic crystal
system, space group P 21/c, a = 11.0688(9) Å , b = 14.9195(13)
Å , c = 7.8135(7) Å , V = 1263.71(19) Å 3, Z = 4, dcalcd = 1.358
g/cm3, F(000) = 544, 2θ range 1.879~26.477o, R indices (all
data) R1 = 0.0362, wR2 = 0.0852.
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17
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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
(294 mg); Red solid; mp = 176-177 C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ calcd
1
for C23H20NaO4S 415.0980, found 415.0976; H NMR (400
MHz, CDCl3): δ 8.43 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.41 (d,
J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.34-7.29 (m, 3H),
7.12 (dt, J = 0.8, 7.6 Hz, 1H), 7.04 (s, 1H), 6.98 (s, 1H), 3.99
(s, 3H), 3.98 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 152.3, 148.7, 145.7, 144.6, 140.9, 138.9, 138.2,
137.5, 131.1, 129.9 (2x), 126.9 (2x), 126.6, 125.9, 121.4,
121.2, 118.9, 113.0, 102.6, 56.2, 56.1, 21.6. Single-crystal X-
Ray diagram: crystal of compound 9a was grown by slow
diffusion of EtOAc into a solution of compound 9a in CH2Cl2
to yield colorless prisms. The compound crystallizes in the
monoclinic crystal system, space group P 2/c, a = 8.3017(5) Å ,
b = 10.3840(6) Å , c = 21.3810(12) Å , V = 1838.22(19) Å 3, Z =
4, dcalcd = 1.418 g/cm3, F(000) = 824, 2θ range 1.910~26.462o,
R indices (all data) R1 = 0.0385, wR2 = 0.0891.
6-Fluoro-1,2,3-trimethoxy-9-methyl-9H-fluorene (8ab). 8ab
was synthesized according to general synthetic procedure from
8o (440 mg, 1.0 mmol); Yield = 90% (259 mg); White solid;
mp = 86-88 oC (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H17FNaO3
9-Methanesulfonylmethylene-2,3-dimethoxy-9H-fluorene
(9b). 9b was synthesized according to general synthetic proce-
dure from 8b (95 mg, 0.3 mmol); Yield = 68% (215 mg); Red
solid; mp = 178-179 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
1
311.1059, found 311.1052; H NMR (400 MHz, CDCl3): δ
7.35 (dd, J = 4.8, 8.0 Hz, 1H), 7.30 (dd, J = 2.4, 8.8 Hz, 1H),
7.00 (s, 1H), 6.94 (dt, J = 2.4, 8.4 Hz, 1H), 4.02 (s, 3H), 3.95
(q, J = 7.2 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 1.52 (d, J = 7.6
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 162.4 (d, J =
241.0 Hz), 153.8, 150.6, 144.7 (d, J = 2.3 Hz), 142.1 (d, J =
9.1 Hz), 141.8, 135.2 (d, J = 3.1 Hz), 133.8, 124.5 (d, J = 9.1
Hz), 122.9 (d, J = 22.7 Hz), 106.1 (d, J = 22.8 Hz), 99.0, 60.8,
60.4, 56.0, 40.6, 17.4.
1
C17H16NaO4S 339.0667, found 339.0663; H NMR (400 MHz,
CDCl3): δ 8.23 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.42 (d, J =
8.0 Hz, 1H), 7.33 (dd, J = 1.2, 7.6 Hz, 1H), 7.15 (dt, J = 1.2,
7.6 Hz, 1H), 7.04 (s, 1H), 6.94 (s, 1H), 3.98 (s, 3H), 3.93 (s,
3H), 3.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 152.4,
148.8, 147.0, 140.9, 137.8, 137.6, 131.3, 126.8, 125.5, 121.2,
120.4, 118.9, 112.4, 102.8, 56.11, 56.06, 43.3.
2,3,6,7-Tetramethoxy-9-methyl-9H-fluorene (8ac). 8ac was
synthesized according to general synthetic procedure from 8q
(452 mg, 1.0 mmol); Yield = 90% (270 mg); White solid; mp
= 173-175 oC (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H20NaO4
9-(4-Fluorobenzenesulfonylmethylene)-2,3-dimethoxy-9H-
fluorene (9c). 9c was synthesized according to general syn-
thetic procedure from 8c (119 mg, 0.3 mmol); Yield = 60%
1
o
323.1259, found 323.1253; H NMR (400 MHz, CDCl3): δ
(238 mg); Red solid; mp = 218-219 C (recrystallized from
7.16 (s, 2H), 7.01 (s, 2H), 3.99 (s, 6H), 3.94 (s, 6H), 3.78 (q, J
= 7.6 Hz, 1H), 1.47 (d, J = 7.6 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 148.7 (2x), 148.0 (2x), 141.5 (2x), 133.2 (2x),
107.5 (2x), 102.3 (2x), 56.19 (2x), 56.16 (2x), 42.1, 18.5. Sin-
gle-crystal X-Ray diagram: crystal of compound 8ac was
grown by slow diffusion of EtOAc into a solution of com-
pound 8ac in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the orthorhombic crystal system, space group P
m n 21, a = 14.7692(17) Å , b = 10.2619(12) Å , c = 5.9666(6)
Å , V = 904.30(17) Å 3, Z = 2, dcalcd = 1.415 g/cm3, F(000) =
404, 2θ range 1.985~26.640o, R indices (all data) R1 = 0.0304,
wR2 = 0.0795.
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ calcd
1
for C22H17FNaO4S 419.0729, found 419.0722; H NMR (400
MHz, CDCl3): δ 8.40 (s, 1H), 8.07-8.03 (m, 2H), 7.40 (d, J =
8.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H),
7.23-7.18 (m, 2H), 7.11 (dt, J = 0.8, 8.4 Hz, 1H), 7.03 (s, 1H),
6.92 (s, 1H), 3.99 (s, 3H), 3.96 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 165.6 (d, J = 254.7 Hz), 152.5, 148.7, 146.2,
140.9, 138.1, 137.9 (d, J = 3.0 Hz), 137.6, 131.2, 129.7 (d, J =
9.1 Hz, 2x), 126.7, 125.6, 121.2, 120.6, 118.9, 116.6 (d, J =
22.0 Hz, 2x), 112.9, 102.7, 56.1, 56.0. Single-crystal X-Ray
diagram: crystal of compound 9c was grown by slow diffusion
of EtOAc into a solution of compound 9c in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group P 2/c, a = 8.3081(3) Å , b =
10.2495(3) Å , c = 20.9221(7) Å , V = 1775.85(10) Å 3, Z = 4,
dcalcd = 1.483 g/cm3, F(000) = 824, 2θ range 1.953~26.448o, R
indices (all data) R1 = 0.0397, wR2 = 0.0951.
General synthetic procedure of compounds 9a-9d and 9m-
9n is as follows: 8a-8d and 8m-8n (0.3 mmol) and iodine (100
o
mg, 0.4 mmol) was dissolved in EtOAc (30 mL) at 25 C.
Then, 1,2-epoxybutane (440 mg, 6.0 mmol) was added to the
reaction mixture and the reaction mixture was irradiated under
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2,3-Dimethoxy-9-(4-methoxybenzenesulfonylmethylene)-
2.16 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 151.0,
9H-fluorene (9d). 9d was synthesized according to general
synthetic procedure from 8d (122 mg, 0.3 mmol); Yield =
148.9, 144.5, 144.4, 141.9, 136.7, 136.6, 135.2, 129.8 (2x),
129.5, 129.1 (2x), 128.12, 128.06 (2x), 127.9 (3x), 126.5,
126.3, 118.7, 109.0, 102.2, 74.5, 56.1, 55.9, 54.3, 21.5, 21.4.
Single-crystal X-Ray diagram: crystal of compound 10a was
grown by slow diffusion of EtOAc into a solution of com-
pound 10a in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group P
21/c, a = 20.676(2) Å, b = 14.0649(14) Å , c = 9.2725(8) Å , V
= 2637.9(4) Å 3, Z = 4, dcalcd = 1.381 g/cm3, F(000) = 1152, 2θ
range 1.007~26.485o, R indices (all data) R1 = 0.1252, wR2 =
0.2791.
o
62% (253 mg); Red solid; mp = 183-184 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+
1
calcd for C23H20NaO5S 431.0929, found 431.0921; H NMR
(400 MHz, CDCl3): δ 8.45 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H),
7.40 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (t, J =
7.6 Hz, 1H), 7.10 (dt, J = 0.8, 7.6 Hz, 1H), 7.03 (s, 1H), 6.98
(d, J = 9.2 Hz, 2H), 6.96 (s, 1H), 3.980 (s, 3H), 3.976 (s, 3H),
3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 163.6,
152.2, 148.7, 145.1, 140.8, 138.2, 137.4, 133.4, 131.0, 129.1
(2x), 126.5, 125.8, 121.8, 121.1, 118.8, 114.4 (2x), 112.9,
102.5, 56.1, 56.0, 55.6.
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6-Fluoro-9-methanesulfonylmethyl-2,3-dimethoxy-9H-
fluoren-9-ol (10b). NaOH (160 mg, 4.0 mmol) was added to a
solution of 8n (334 mg, 1.0 mmol) in a cosolvent of H2O (5
6-Fluoro-2,3-dimethoxy-9-(toluene-4-sulfonylmethylene)-
9H-fluorene (9m). 9m was synthesized according to general
synthetic procedure from 8m (123 mg, 0.3 mmol); Yield =
o
mL) and dioxane (10 mL) at 25 C. The reaction mixture was
stirred at reflux for 15 h. The reaction mixture was cooled to
o
o
68% (279 mg); Red solid; mp = 186-187 C (recrystallized
25 C, and extracted with EtOAc (3 x 15 mL). The combined
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+
organic layers were washed with brine, dried, filtered, and
evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexanes/EtOAc = 4/1-1/1) afforded
compound 10b. Yield = 63% (222 mg); Red liquid; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C17H17FNaO5S 375.0678,
1
calcd for C23H19FNaO4S 433.0886, found 433.0880; H NMR
(400 MHz, CDCl3): δ 8.45 (s, 1H), 7.92 (dd, J = 1.6, 8.4 Hz,
2H), 7.38-7.33 (m, 3H), 7.11 (dd, J = 2.4, 8.4 Hz, 1H), 7.00 (s,
1H), 6.90 (s, 1H), 6.80 (dt, J = 2.4, 8.4 Hz, 1H), 3.993 (s, 3H),
3.990 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 165.3 (d, J = 248.6 Hz), 152.3, 149.3, 145.7, 144.5, 143.4 (d,
J = 9.1 Hz), 138.9, 136.0, 133.9 130.0 (2x), 127.0 (2x), 126.7,
122.7 (d, J = 9.9 Hz), 121.6 (d, J = 2.3 Hz), 113.1 (d, J = 23.5
Hz), 113.0, 106.7 (d, J = 23.5 Hz), 102.8, 56.2, 56.1, 21.6.
1
found 375.0672; H NMR (400 MHz, CDCl3): δ 7.89 (dd, J =
6.0, 8.8 Hz, 1H), 7.21 (dt, J = 2.8, 8.4 Hz, 1H), 7.10 (s, 1H),
7.04 (dd, J = 2.8, 8.8 Hz, 1H), 6.76 (s, 1H), 4.23 (dd, J = 0.8,
14.8 Hz, 1H), 3.99 (dd, J = 0.4, 14.8 Hz, 1H), 3.96 (br s, 1H),
3.93 (s, 3H), 3.86 (s, 3H), 3.05 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 191.1, 164.5 (d, J = 254.7 Hz), 149.9, 148.8,
143.4 (d, J = 9.1 Hz), 134.3 (d, J = 3.0 Hz), 132.0 (d, J = 9.8
Hz), 131.4, 119.0 (d, J = 21.9 Hz), 115.6, 115.5 (d, J = 22.0
Hz), 113.2, 112.4, 63.3, 56.3, 56.2, 42.0.
6-Fluoro-9-methanesulfonylmethylene-2,3-dimethoxy-9H-
fluorene (9n). 9n was synthesized according to general syn-
thetic procedure from 8n (100 mg, 0.3 mmol); Yield = 77%
o
(257 mg); Red solid; mp = 188-189 C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ calcd
2,3-Dimethoxy-9-[1-(toluene-4-sulfonyl)ethyl]-9H-fluoren-
1
for C17H15FNaO4S 357.0573, found 357.0568; H NMR (400
9-ol (10c). CuBr2 (450 mg, 2.0 mmol) was added to a solution
o
MHz, CDCl3): δ 8.28 (s, 1H), 7.44 (dd, J = 5.2, 8.8 Hz, 1H),
7.14 (dd, J = 2.4, 8.4 Hz, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 6.86
(dt, J = 2.4, 8.8 Hz, 1H), 4.01 (s, 3H), 3.96 (s, 3H), 3.22 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.5 (d, J = 249.4
Hz), 152.5, 149.5, 146.0, 143.4 (d, J = 9.1 Hz), 136.2, 133.5,
126.4, 122.8 (d, J = 9.8 Hz), 120.5 (d, J = 11.5 Hz), 113.4 (d, J
= 23.5 Hz), 112.5, 106.9 (d, J = 24.2 Hz), 103.0, 56.3, 56.2,
43.4.
of 2l (270 mg, 1.0 mmol) in EtOAc (15 mL) at 25 C. The
reaction mixture was stirred at 60 oC for 15 min. Then,
TolSO2Na 6a (196 mg, 1.1 mmol) was added to the reaction
o
mixture. The reaction mixture was stirred at 60 C for 15 h.
o
The reaction mixture was cooled to 25 C, neutralized with
saturated NaHCO3(aq) (30 mL), and extracted with EtOAc (3 x
15 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 =
10/1-2/1) afforded compound 10c. Two isomers; Ratio = 1:1;
Yield = 35% (148 mg); White solid; mp = 150-153 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C24H24NaO5S 447.1242, found
2,3-Dimethoxy-9-(toluene-4-sulfonyl)-9-(toluene-4-
sulfonylmethyl)-9H-fluorene (10a). TolSO2Na (710 mg, 4.0
mmol) was added to a solution of 8a (392 mg, 1.0 mmol) in a
o
cosolvent of H2O (5 mL) and dioxane (10 mL) at 25 C. The
reaction mixture was stirred at reflux for 15 h. The reaction
1
o
447.1235; H NMR (400 MHz, CDCl3): δ 8.02-8.00 (m, 1H),
mixture was cooled to 25 C, and extracted with EtOAc (3 x
7.63 (s, 1/2H), 7.57 (s, 1/2H), 7.38-7.20 (m, 3H), 6.89 (s,
1/2H), 6.83 (s, 1/2H), 6.77-6.70 (m, 4H), 5.53-5.44 (m, 1H),
4.06 (s, 3/2H), 4.05 (s, 3/2H), 3.92 (s, 3/2H), 3.89 (s, 3/2H),
2.20 (d, J = 6.8 Hz, 3/2H), 2.16 (s, 3H), 2.07 (d, J = 6.8 Hz,
3/2H), 1.60 (br s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
151.0 (1/2x), 150.8 (1/2x), 149.3 (1/2x), 149.0 (1/2x), 143.9
(1/2x), 143.8 (1/2x), 142.6 (1/2x), 141.5 (1/2x), 140.5 (1/2x),
138.0 (1/2x), 135.9 (1/2x), 134.7 (1/2x), 132.9 (1/2x), 132.2
(1/2x), 129.8 (1x), 129.7 (1/2x), 129.6 (1/2x), 129.3 (1x),
129.2 (1x), 127.93 (1x), 127.92 (1x), 127.0 (1/2x), 126.6
(1/2x), 126.4 (1/2x), 125.9 (1/2x), 118.9 (1/2x), 118.6 (1/2x),
110.0 (1/2x), 109.0 (1/2x), 102.4 (1/2x), 102.1 (1/2x), 80.0
15 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 =
4/1-1/1) afforded compound 10a. Yield = 70% (384 mg); Red
solid; mp = 197-198 oC (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
1
C30H28NaO6S2 571.1225, found 571.1221; H NMR (400 MHz,
CDCl3): δ 7.67 (dd, J = 1.6, 7.2 Hz, 1H), 7.28 (dt, J = 0.8, 8.4
Hz, 1H), 7.17-7.14 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.95 (s,
1H), 6.94 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 6.71 (d, J = 8.4 Hz,
2H), 6.65 (d, J = 8.4 Hz, 2H), 4.69 (d, J = 14.8 Hz, 1H), 4.63
(d, J = 14.8 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 2.32 (s, 3H),
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The Journal of Organic Chemistry
(1/2x), 79.9 (1/2x), 56.4 (1x), 56.0 (1x), 47.9 (1/2x), 47.8
Supporting Information
2
3
(1/2x), 23.6 (1/2x), 23.5 (1/2x), 21.4 (1x).
Scanned photocopies of NMR spectral data for all compounds and
X-ray analysis data of 2g, 7a, 8b-c, 8e, 8h, 8s-t, 8v, 8y, 8aa, 8ac,
9a, 9c, 10a, DFT results and optimized coordinates. This infor-
mation is available free of charge via the Internet at http:
//pubs.acs.org.
4
5
6
9-(Toluene-4-sulfonylmethyl)-9H-fluorene (11a). NaBH4
(50 mg, 1.3 mmol) was added to a stirred solution of 7j (350
mg, 1.0 mmol) in a cosolvent of THF and MeOH (10 mL, v/v
o
o
= 1/1) at 25 C. The reaction mixture was stirred at 25 C for
30 min, and the solvent was concentrated. The residue was
diluted with water (10 mL), and the mixture was extracted
with CH2Cl2 (3 x 30 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Without further purifi-
cation, BF3·OEt2 (185 mg, 1.3 mmol) was added to the stirred
solution of the resulting β-hydroxysulfone in CH2Cl2 (10 mL)
7
8
9
AUTHOR INFORMATION
Corresponding Author
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*Email: mychang@kmu.edu.tw
*Email: hychen@kmu.edu.tw
ORCID
at 25 oC. The reaction mixture was stirred at 25 C for 30 min,
o
Meng-Yang Chang: 0000-0002-1983-8570
Hsing-Yin Chen: 0000-0003-3948-8915
Notes
and the solvent was concentrated. The residue was diluted
with saturated NaHCO3(aq) (10 mL) and the mixture was ex-
tracted with CH2Cl2 (3 x 30 mL). The combined organic layers
were washed with brine, dried, filtered and evaporated to
affoard crude product under reduced pressure. Purification on
silica gel (hexanes/EtOAc = 20/1~10/1) afforded compound
The authors declare no competing financial interest.
ACKNOWLEDGMENT
o
11a. Yield = 89% (297 mg); White solid; mp = 138-139 C
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).
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C21H18NaO2S 357.0925, found
1
357.0920; H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.0 Hz,
2H), 7.72 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.40-
7.36 (m, 4H), 7.30 (dt, J = 1.2, 7.6 Hz, 2H), 4.48 (t, J = 5.6 Hz,
1H), 3.59 (d, J = 5.6 Hz, 2H), 2.47 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 145.0 (2x), 144.8 (2x), 140.7, 136.6,
130.1 (2x), 128.1 (2x), 127.8 (2x), 127.5 (2x), 125.1 (2x),
119.9 (2x), 60.5, 41.4, 21.6.
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Gram-Scale Synthesis of Compound 8a. CuBr2 (1.79 g, 8.0
mmol) was added to a solution of 2a (1.0 g, 3.9 mmol) in
o
EtOAc (40 mL) at 25 C. The reaction mixture was stirred at
o
60 C for 15 min. Then, TolSO2Na 6a (800 mg, 4.5 mmol)
was added to the reaction mixture. The reaction mixture was
o
stirred at 60 C for 18 h. The reaction was monitored by TLC.
o
The reaction mixture was cooled to 25 C, neutralized with
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DFT calculation. The M06-2X-D3 method was employed
for the present DFT calculations. The elements Cu and Br
were described by the SDD basis sets with effective core po-
tentials, whereas the remaining elements were described by 6-
31G* basis sets. Geometry optimizations and vibrational fre-
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gle-point-energy calculations. The solvent effect (solvent =
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calculations were achieved by using the Gaussian 09 pro-
gram.41
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