Copper-Catalyzed Radical Cascade Cyclization to Access 3-Sulfonated Indenones with the AIE Phenomenon

Article abstract of DOI:10.1021/acs.joc.8b02175

An efficient copper-catalyzed radical cascade cyclization strategy was developed, by which a wide variety of 3-sulfonyl substituted indenones were prepared in one pot via reaction of 2-alkynylbenzonitriles with sulfonyl hydrazides in the presence of TBHP and CuI under mild reaction conditions. Much more importantly, the 3-sulfonyl indenones, synthesized through our newly developed copper-catalyzed radical cascade cyclization strategy, were found to own typical aggregation-induced emission (AIE) properties, showing orange to red emission with large Stokes shift (more than 135 nm). In addition, such newly found AIEgens could be successfully used in live cell imaging, exhibiting excellent biocompatibility and application potential.

Full text of DOI:10.1021/acs.joc.8b02175

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Article
Copper-Catalyzed Radical Cascade Cyclization to
Access 3-Sulfonated Indenones with AIE Phenomenon
Kai Sun, Xiao-Lan Chen, Shi-Jun Li, Dong-Hui Wei, Xiao-Ceng Liu, Yin-Li Zhang,
Yan Liu, Lu-Lu Fan, Ling-Bo Qu, Bing Yu, Kai Li, Yuan-Qiang Sun, and Yufen Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02175 • Publication Date (Web): 01 Nov 2018
Downloaded from http://pubs.acs.org on November 1, 2018
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Copper-Catalyzed Radical Cascade Cyclization to Access 3-
Sulfonated Indenones with AIE Phenomenon
a
a,b
a
a
a
Kai Sun, Xiao-Lan Chen, * Shi-Jun Li, Dong-Hui Wei, Xiao-Ceng Liu, Yin-Li Zhang,
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a
Yan Liu,a,c Lu-Lu Fan, Ling-Bo Qu, Bing Yu, * Kai Li, * Yuan-Qiang Sun, * and Yu-
a
a
a,
a,
a,
Fen Zhaoa,b.
a
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China.
b
The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005, China.
c
College of biological and pharmaceutical engineering, Xinyang Agriculture & Forestry University, Xinyang,
464000, China
E-mail: chenxl@zzu.edu.cn; bingyu@zzu.edu.cn; likai@zzu.edu.cn; sunyq@zzu.edu.cn.
R3
R1
+
O
CuI (20 mol%)
TBHP (4 equiv.)
S
O
O
R3 S NHNH2
R1
R2
R2
O
CH3CN/H2O
CN
60 °C, 8 h
O
R2 = H ,CH , F, Cl, Br; R , R = aryl
1
3
Cell imaging
AIE Phenomenon
3
efficient method to 3-sulfoned indenones
DFT calculation
successfully used in live cell imaging
novel AIEgens
ABSTRACT: An efficient copper-catalyzed radical cascade cyclization strategy was
developed, by which a wide variety of 3-sulfonyl substituted indenones were prepared in
one-pot via reaction of 2-alkynylbenzonitriles with sulfonyl hydrazides in the presence of
TBHP and CuI under mild reaction conditions. Much more importantly, the 3-sulfonyl
indenones, synthesized through our newly developed copper-catalyzed radical cascade
cyclization strategy, were found to own typical aggregation-induced emission (AIE)
properties, showing orange to red emission with large stokes shift (more than 135 nm). In
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addition, such newly found AIEgens could be successfully used in live cell imaging,
exhibiting excellent biocompatibility and application potential.
Introduction
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AIE phenomenon was first reported by Tang et al in 2001. Most of the traditional
luminogens exhibit weak luminescence in solid or aggregated state due to the notorious
2
aggregation-caused quenching (ACQ) effect. On contrast, AIEgens shows excellent
luminescene properties in solid or aggregated state, which have been widely used in the
development of biosensors, organic light-emitting diodes, stimuli-responsive materials,
3
and so on. To date, numbers of classic AIEgens have been developed including
tetraphenylethene (TPE), tetraphenylpyrazine (TPP), hexaphenylsilole (HPS),
salicylaldehyde hydrazine, salicyladazine (SA) 2,5-bis(4-alkoxycarbonylphenyl)-1,4-
4
diaryl-1,4-dihydropyrrolo[3,2-b]pyrrole (AAPP). Nevertheless, the number and type of
the core structure of AIEgens are still very limited. The development of new AIEgens with
a facile synthesis process and excellent luminescence properties remains challenging and
in great need.
Cascade reaction, also known as “tandem” reaction, has emerged as one of the most
5
promising and powerful synthetic strategies in organic chemistry. The distinguished
merits of cascade reaction include high atom economy and great reduction of work and
6
time required to carry them out. Among the diverse cascade methodologies, strategies
using free-radical cascade reactions are highly valuable because they enable to synthesize
7
complex and usually poly molecular skeletons in only few synthetic steps. Despite the
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promising achievement that has been made in the recent past few years, the development
of specific free-radical cascade reactions with high regioselectivity or stereoselectivity is
still highly expected.
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Indenones are privileged structural motifs that exist in natural products and many
8
synthetic compounds with various biologically activities. For example, Euplectin, a
naturally occurring product with an indenone moiety, exhibits a strong anti-tumor activity.9
Some indenones are also important alcoholic fermentation activators.10 Meanwhile,
indenones have frequently been employed as starting materials in preparation of a great
number of biologically and photochemically important molecules, such as estrogen
receptor,11 C-nor-D-homo steroids,12 gibberellins,13 substituted naphthalenes,14 and
photochromic indenones15 etc. The preparation of indenones has thus triggered great
interest among synthetic chemists in past decades. The two classical synthetic strategies
for indenones involve intramolecular Friedel-Crafts acylation16 and Grignard reagent-
17
initiated reactions . However, the classical methods require harsh reaction conditions, and
thus suffer from practical inconvenience. In 1989, Heck et al first reported the synthesis of
2
,3-diphenyl-1-indenone from o-iodobenzaldehyde and diphenylacetylene (Scheme 1a),18
and since then the palladium- or rhodium-catalyzed annulation reactions of ortho-
1
9
bifunctionalized arenes with alkynes have been extensively explored (Scheme 1b). In
recent years, Rh-catalyzed annulations of aryl aldehydes, nitriles, or amides with alkynes
2
0
towards indenone derivatives have appeared (Scheme 1c). Nevertheless, the high cost of
the precious metal catalysts (Rh, Pd, etc.), and the poor regioselectivity when
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unsymmetrical alkynes were employed as reactant, might limit their synthetic
application.19f Very recently, Lei’s group provided a powerful radical cascade cyclization
method for construction of 2-sulfonated indenones from ynones and sulfinic acids (Scheme
0
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1d). Similar radical cascade synthesis methods have also successively been adopted to
synthesize several other 2-substituted indenones, including 2-phophsphoryl, cycloalkyl,
and phenylthioindenones.22 It is especially worth mentioning here that, even though
significant progress has been made in the construction of various 2-functionalized
indenones, however, only two types of 3-substituted indenones, 3-phosphorylindenones
2
3
and 3-alkylindenones can be seen synthesized by the group of Tu. Scheme 1e shows Tu’s
synthetic method towards 3-phosphorylindenones, and however, up to two stoichiometric
amounts of sliver salt were necessarily required for this cascade cyclization.23a The similar
drawback also can be seen in another recent method developed by Tu’s group towards 3-
alkylindenones.23b It is well known that sulfonyl-containing molecules are widely found in
marketed drugs and valuable synthetic intermediates. The introduction of sulfonyl groups
2
4
into the aromatic compounds has gained considerable attention over recent years. As part
of our continuing interest in the development of novel synthetic methodologies to
synthesize various aromatic sulfones,25 herein we present a novel and efficient CuI-
catalyzed radical cascade cyclization to access a large variety of 3-sulfonyl indenones, by
reacting various 2-alkynylbenzonitriles with different sulfonyl hydrazides in one-pot under
mild reaction conditions (Scheme 1g). While submitting this manuscript, Tu et al published
26
a Cu(OTf) -catalyzed procedure for 3-sulfonyl indenones construction (Scheme 1f). They
2
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used a much more expensive a copper (II) salt, Cu(OTf) as the catalyst. In contrast, we
2
used CuI, a much cheaper and easily available copper (I) salt, as our catalyst. In the
mechanism they proposed, the role of Cu(II) salt is only to facilitate to generate sulfonyl
radicals that triggered the following cyclization process. However, in our reaction pathway,
we pointed out in this paper that Cu(I) salt participated and took an indispensable role for
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the whole radical cyclization. In particular, a DFT calculation was further carried out to
Previous works:
O
Ph
NaOAc
H
(
a)
+
+
Ph
Ph
Ph
DMF, 120 °C
I
O
R2
R1
R1
FG1
Pd or Rh
R1
R2
(b)
+
FG2
R2
O
O
1
2
FG /FG = CN/I; CHO/halo; CN/B(OH)2; etc.
poor regioselectivity
1
2
R , R = aryl, alkyl.
O
FG
H
R1
R2
Rh Cat.
R1
(c)
+
R2
FG = CN, CHO, C(O)NH2 etc. R , R2 = aryl, alkyl.
1
Pt (+) | Pt (-)
undivided cell
constant current
O
Ar
3
O
S
R2 SO H
2
R1
R2
(d)
R1
+
TBAI, LiClO4
CH3CN/H2O
2
Ar
1
O
O
ynones
2-sulfonated indenones
R2
Ar
O
P
R3
O
(
e) R1
AgNO3 (2 equiv.)
R2
R1
+
H
P
R3
Ar
CH3CN, H2O, 80 °C
CN
O
Just Publised Cu(OTf)2 Catalyzed Radical Cyclization:
R3
R1
O
S
O
O
Cu(OTf)2, TBHP
R1
R2
+
R2
(f)
R3
S
NHNH2
CH3CN/H2O
80 °C, 4 h
O
CN
O
This work: CuI Catalyzed Radical Cyclization:
R3
R1
O
S
3
CuI (20 mol%)
TBHP (4 equiv.)
O
O
S
(g)
R2
+
R3
NHNH2
R2
R1
CH3CN/H2O
60 °C, 8 h
2
O
1
CN
O
R2 = H ,CH3, F, Cl, Br; R , R3 = aryl
1
AIE Phenomenon
Scheme 1. Comparision with previous works
highlight the essential role of CuI in the radical cascade cyclization. Much more
importantly, our newly synthesized 3-sulfonyl substituted indenones were found to own
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typical aggregation-induced emission (AIE) properties. These compounds show orange to
red emission with large stokes shift (more than 135 nm). In addition, such novel AIEgens
can be successfully used in live cell imaging, which exhibited excellent biocompatibility.
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Results and Discussion
We initiated our study by establishing optimal experimental conditions using the
model reaction of 2-(phenylethynyl)benzonitrile 1a with TsNHNH 2a (Table 1). It is
2
pleased that, when the reaction was performed using 10 mol% CuI and 2 equiv. of TBHP
in CH CN/H O (v/v = 3/1), the desired product 3a was obtained in 40% yield (entry 1).
3
2
However, the yields were not improved by using other copper catalysts, such as CuBr,
CuCl, Cu O, and CuSO (entries 2-5). Subsequently, several other commonly used
2
4
catalysts were tested as shown in entries 6-11. The results showed that FeSO and FeCl
4
3
did not exhibit better reactivity than CuI (entries 6 and 7), and I , TBAI, NH I as well as
2
4
KI gave no product as well (entries 8-11). It is pleased to see that, the yield of 3a increased
to 48% along with the increase of the amount of CuI from 10 mol% to 20 mol% (entry 12)
and then ceased to increase as the amount of CuI continued to increase up to 30 mol%
(
entry 13). After that, several other oxidants, such as DTBP, BPO, and K S O were
2 2 8
investigated, and unfortunately, no satisfied results were observed (entries 14-16). To our
delight, when the amount of TBHP was increased to 4 equiv., a satisfied yield of 3a was
obtained (72%, entry 18), and afterwards, a slight decrease was observed when 5 equiv. of
TBHP was employed (entry 19). Furthermore, several different solvent systems were tested
as shown in entries 20-25, however, no improved yields were obtained. Investigation on
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Table 1. Optimization of reaction conditions[a]
Ph
Ts
O
catalyst, oxidant
TsNHNH2
Ph
+
solvent (v/v = 3/1)
Temp., time
CN
1a
2a
3a
Yield[b]
%
Entry
Catalyst (mol%)
CuI (10)
Oxidant
Solvent
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
DTBP (2)
BPO (2)
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O
40
38
CuBr (10)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
CuCl (10)
35
Cu
CuSO
FeSO
FeCl
2
O (10)
27
4
(10)
(10)
(10)
29
4
23
3
29
I
2
(10)
TBAI (10)
NH I (10)
ND[c]
ND[c]
ND[c]
ND[c]
48
1
1
0
1
4
KI (10)
CuI (20)
CuI (30)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
--
12
1
1
1
1
1
1
3
4
5
6
7
8
47
ND[c]
35
K
2
S
2
O
8
(2)
40
TBHP (3)
TBHP (4)
TBHP (5)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (4)
TBHP (2)
--
59
72
19
70
2
2
0
1
DMSO/H
DMF/H
EtOH/H
2
O
Trace[c]
Trace[c]
2
O
22
2
O
Trace[c]
Trace[c]
2
2
2
3
4
5
2
THF/H O
DCE/H
2
O
35
57
2
Acetone/H O
2
2
6[d]
7[e]
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CN/H
CN/H
CN/H
CN/H
CN/H
CN/H
2
2
2
2
2
2
O
O
O
O
O
O
29
67
2
8[f]
29[g]
54
71
3
3
0
1
ND[c]
ND[c]
CuI (20)
[
a]
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10-20 mol%), oxidant (2-5 equiv.),
solvent (2 mL) at 60 °C for 8 h. TBHP = tert-butyl hydroperoxide (70% aqueous solution), TBAI =
tetrabutylammonium iodide, DTBP = Di-tert-butyl peroxide, BPO = benzoyl peroxide, DCE = 1,2-
dichloroethane, ND = Not detected. [b] Isolated yields. [c] Detected by TLC. [d] At 40 ºC. [e] At 80 °C.
[
f]
For 4 h. [g] For 12 h.
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
temperature as well as time on the reaction were also performed, and the results showed
that 60 °C and 8 h were still the best choices (entries 26-29). Further tests indicated that
the reaction did not occur in the absence of either CuI or TBHP (entries 30 and 31). After
intensive experimentation, the optimized reaction conditions were established as follows:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
a (0.2 mmol), 2a (0.4 mmol), CuI (20 mol%) and TBHP (4 equiv.) were mixed in
CH CN/H O (v/v = 3/1) solution at 60 ºC for 8 h.
3
2
With the optimized reaction conditions established, we next explored the substrate scope
by examining various 2-alkynylbenzonitriles 1 and sulfonyl hydrazides 2, and the results
were illustrated in Scheme 2. As it can be seen, various 2-(phenylethynyl)benzonitriles
reacted smoothly with TsNHNH under the optimized conditions, regioselectively giving
2
the resulting 3-sulfonted indenones 3a-i in moderate to good yields (52-78%). Among
them, 2-(phenylethynyl)benzonitriles with electron-donating groups (-Me, -Et, -OMe)
1
attached to phenyl ring in R moieties, resulted in relatively high yields (3b-f, 70-78%),
1
whereas electron-withdrawing groups (-F, -Cl, -Br) in R gave slightly low yields (3g-i, 52-
1
6
5%). It was observed that a substrate with a sterically hindered R group (pyrenyl group)
was also suitable for this transformation, although the corresponding product 3j was
obtained in relatively low yield. Furthermore, 2-(phenylethynyl)benzonitriles with
2
different R groups were employed to react with TsNHNH , yielding the desired products
2
3k-n in good yields (65-77%). Electronic effects were also observed in those cases. 2-
(phenylethynyl)benzonitriles with electron-withdrawing groups (6-Cl, 6-Br, 7-F) rendered
higher yields (3l-n, 73-77%), compared to those with electron-donating groups (6-Me, 3k).
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Finally, 2-(phenylethynyl)benzonitrile 1a was employed to react with various sulfonyl
3
hydrazides bearing different R groups under the optimized reaction conditions, giving the
corresponding products 3o-x in moderate to good yields.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R3
R1
O
S
CuI (20 mol%)
TBHP (4 equiv.)
O
O
S
R2
R3
R1
+
NHNH2
R2
CH3CN/H2O
CN
O
6
0 oC, 8 h
O
1
2
3
Ts
O
Me
Me
R1
R1 =
Me
Et
3a, 72%
3b, 76%
3c, 73%
3d, 70%
3e, 77%
OMe
F
Cl
Br
3f, 78%
3g, 52%
3h, 58%
3i, 65%
3j, 34%
Ts
3
4
7
R2 = 6-CH3
R2 = 6-Cl
R2 = 6-Br
R2 = 7-F
5
6
R2
2
1
3k, 65%
3l, 74%
3m, 73%
3n, 77%
O
R3
Me
Me
O
S
O
R3
=
tBu
OMe
3o, 63%
3p, 65%
3q, 67%
3v, 68%
3r, 74%
3s, 75%
3x, 45%
O
F
Cl
Br
I
CF3
3t, 58%
3u, 63%
3w, 70%
Reaction conditions: 2-(arylethynyl)benzonitriles 1 (0.2 mmol), sulfonyl hydrazides 2 (0.4
o
mmol), CuI (20 mol%), TBHP (4 equiv.), CH
Isolated yields were provided.
3 2
CN/H O (v/v = 3/1) as solvent (2 mL), 60 C, 8 h.
Scheme 2. Substrate scope for the synthesis of 3-sulfonated indenones
We then carried out several control experiments to explore the reaction mechanism
Scheme 3). When TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl) and BHT (2,6-
(
di-tert-butyl-4-methylphenol), two widely used radical scavengers, were added into the
reaction system, respectively, no desired product 3a was observed in each case, suggesting
that the reaction might proceed via a radical process (Scheme 3a-b). It is worth reminding
that when the control reaction was performed with BHT under optimized reaction condition
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2
3
4
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
Scheme 3b), products 9 has been successfully separated and identified, indicating that
2
7
tosyl radical (Ts·) was produced in the reaction process (for details see Fig S1). It was
reported that TBAI together with TBHP can effectively assist the generation of sulfonyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
8
radicals from sulfonyl hydrazides. Thus we carried out a control experiment using TBAI
together with TBHP as tosyl radical promoter (Scheme 3c). The result showed that
compound 9 was also generated in the reaction process (Figure S2). Finally, an isotopic
1
8
18
labeling experiment with H O was conducted (Scheme 3d), affording O-lableled 3a
2
(Figure S3). That meant the carbonyl oxygen in 3a was originated from H O instead of O
2 2
in the air. It was experienced here that, in every control experiment (Scheme 3a-d), after
catalyst CuI or the tosyl radical promoter (TBAI/TBHP) was added to the reaction solution,
the formation of bubbles in the solution was always observed.
Ph
Ts
TEMPO (3 equiv.)
(a)
+
TsNHNH2
Ph
Standard conditions
CN
O
1a
2a
3a (0%)
OH
Ph
Ts
tBu
tBu
BHT (3 equiv.)
+
TsNHNH2
Ph
+
(b)
Standard conditions
CN
O
Ts
1a
2a
3a (0%)
9 (Yield: 22%)
OH
TBAI (20 mol%)
BHT (3 equiv.)
TBHP (4 equiv.)
Ph
Ts
tBu
tBu
(c)
+
TsNHNH2
Ph
+
CH3CN/H2O
CN
6
0 oC, 8 h
O
Ts
9
(Yield: 18%)
1a
2a
3a (0%)
Ts
Ph
Ts
CuI (20 mol%)
TBHP (4 equiv.)
+
Ph
(d)
+
TsNHNH2
Ph
CH3CN/H218
0 oC, 8 h
O
CN
6
16O
18O
1a
2a
Yield: 70 %
Scheme 3. Control experiments
The mechanism is proposed based upon our experimental outcomes and literature
reports, as shown in Scheme 4. Initially, TBHP reacts with CuI to produce tert-butoxyl
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29
radical (t-BuO·) and tert-butylperoxy radical (t- BuOO·). Then, successive H-abstraction
of sulfonyl hydrazide 2 by the resultant radicals yields sulfonyldiazene radical 4, which
2
4b
subsequently releases molecular N , affording sulfonyl radical 5. Then, a cascade
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
cyclization is triggered by sulfonyl radical 5. Initially, sulfonyl 5 regioselectively adds to
the C-C triple bond of 2-alkynylbenzonitriles 1, giving radical 6, which immediately
undergoes an intramolecular cyclization, rendering the iminyl radical 7. Afterwards, the
coupling of radical 7 with Cu(OH)I yields the intermediate 8, which subsequently abstracts
a hydrogen atom from t-BuOOH to give imine 10. Finally, imine 10 undergoes in situ
hydrolysis to yield the target products 3. Again, it can be seen from scheme 4 that iodide
-
anion (I ) from CuI can react with t-BuOOH to generate tert-butoxyl radical (t-BuO·) which
is capable of reacting with sulfonyl hydrazide 2 to give tosyl radical. However, it was
observed from entry 7 of Table 1 that there was in fact no target product 3a obtained
without participation of CuI, even with the presence of tosyl radical 5 generated by reacting
sulfonyl hydrazide 2 with radical promoter (TBAI/TBHP), making it clear that the copper
ion is indispensable for the following tosyl radical-initiated cascade cyclization reaction.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
t-BuOOH
t-BuO
+
t-BuOOH
t-BuO
+
OH
OH
Cu+
Cu2+
I
1/2 I2
t-BuOO +H2O
t-BuOOH + OH
t-BuOO +H2O
t-BuOOH + OH
R
t-BuOO
or t-BuO
Ar
O S
O
N
O
S
O
2
O
O
Ar
R
NHNH2
R
S
N
N
R
S
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t-BuOOH
O
4
N2
O
5
CN
1
or t-BuOH
6
Cyclization
R
R
S
R
S
R
S
O
O
O
O
S
O
CuII
OH
O
O
O
I
H2O
TBHP
Ar
Ar
Ar
Ar
NH
CuI(OH)(t-BuOO)
N
CuIII
OH
N
O
I
10
8
7
3
Scheme 4. Proposed mechanism
In order to explore the possible reaction pathways, we have systematically studied and
compared non-Cu-catalyzed pathway with Cu-catalyzed pathway by performing DFT
calculations (Figure 1), which have been widely used in the mechanisms of organometallic
3
0
reactions. As shown in Figure 1, both of two reaction pathways share the same structural
transformation from 1a to intermediate 14. Firstly, the radical 11 would like to attack on
the C-C triple bond of 1a to form the C–S bond via transition state TS1, and then the
intramolecular cyclization leads to the radical 13 via transition state TS2. The energy
barriers are 8.9 and 9.9 kcal/mol via TS1 and TS2, respectively. For the non-Cu-catalyzed
pathway, the radical 13 reacts with t-BuOOH to form the intermediate 14 via transition
state TS3, and the energy barrier is only 1.1 kcal/mol. Alternatively, the Cu(II) coordinates
with radical 13 to form a stable intermediate 15, which could easily obtained via transition
state TS3'. It should be mentioned that the energy barrier via TS3' is 1.9 kcal/mol without
the zero point vibrational correction, but this process would become a barrierless process
and the difference between TS3' and 15 would be negative (-3.4 kcal/mol) with zero point
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vibrational correction. For the non-Cu-catalyzed pathway, the energy barrier of the reverse
reaction is 27.2 kcal/mol, showing the process would be reversible. However, with the
assistance of copper, the reverse energy barrier would be up to 54.5 kcal/mol. Therefore,
the 14 only can be irreversibly generated with the presence of Cu salt, which plays an
important role to promote the reaction and stabilize the radical intermediate. All the DFT
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
calculated results are in an agreement with the experimental observations.
O
S
Ph
O
TS3
Ph
TBHP
NH
14
O
S
Ph
S
Ph
S
O
Non-Cu-catalyzed pathway
Ph
O
O
O
N
Ph
TS1
1
1 O
Ph
TS2
Ph
Ph
Ph
S
O
O
S
O
CuII
OH
O
CN
N
I
1
a
12
13
Ph
TS3'
Ph
TBHP
N
5
CuIII
OH
I
NH
1
14
Cu-catalyzed pathway
Non-Cu-catalyzed pathway: ------
Cu-catalyzed pathway: ------
TS2
TS1
15.6
TS2
8.9
TS1
5.7
TS3
12
0.0
0.7
-0.4
1a
TS3
13
-11.6
14+ t-BuOO
-26.4
-29.8
TS3'
15
TS3'
S
O
C
N
H
-38.9
4+ CuI(OH)(t-BuOO)
1
Reaction Coordinate
Figure 1. The energy profile for different reaction pathways (energy: kcal/mol)
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2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The new 3-sulfonyl indenones synthesized through our newly developed copper-
catalyzed radical cascade cyclization strategy were serendipitously found to possess typical
aggregation-induced emission (AIE) properties. As shown in Figure 2A, 3a showed very
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
weak fluorescence in water/EtOH mixtures with water fraction (f ) lower than 80%. When
w
fw was above 80%, intense orange fluorescence could be clearly observed. Water normally
is a poor solvent for most organic molecules, which thus should promote the aggregation
of 3a. The intense fluorescence of 3a in the solutions with high f might be originated from
w
its aggregation, i.e., AIE fluorescence. A direct evidence for the aggregation of 3a was
obtained from dynamic light scattering (DLS) measurements. Particles of around 700 nm
could be detected in the 99% water/EtOH solution, while no particles was observed in the
pure EtOH solution (Figure 2B). Analogous results can be found in Table S2, which means
that 3-sulfonyl indenone core structure is a new AIE system.
Figure 2. A) Fluorescence spectra of 50 μmol/L 3a in EtOH/water mixtures with different
water fractions (f ). Inset: Fluorescence photos of 3a in EtOH/water mixtures (f = 0 and
w
w
9
5
9 vol%), taken under the illumination of a UV lamp. B) Fluorescence intensity of 3a at
77 nm as a function of f . Inset: DLS result of 2 in water.
w
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To further understand the origination of AIE character of 3a, its crystal structure was
3
1
investigated. 3a exist in a typical propeller-like stucture in crystal state (Figure 3). The
o
o
dihedral angle between the conjugate rigid planes are 57.03 and 89.35 , respectively. This
structure feature could effectively weaken the π-π stacking interaction between
neighbouring molecules to avoid fluorescence quenching. As shown in Figure 3, the
minimum distance between the adjacent conjugate planes was as high as 4.08 Å, suggesting
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
that the π-π stacking interaction can be ignored. Meanwhile, the C-C single bond between
the conjugate planes make them rotatable in dissolved state, which effective release the
energy of 3a in excited state. Thus, the excited states of dissolved state often decay or relax
back to the ground state via non-radiative channels, resulting in weak fluorescence.
Figure 3. X-ray crystallography of 3a
The AIE character of 3-sulfonyl indenones endow them with intense fluorescence in
aqueous solution, which make them suitable for the application in cell imaging. The
biological application of compound 3a was then assessed in HeLa cells. Hela cells were
incubated with compound 3a (10 μM) for 15 min and intense fluorescence in red channel
was noted (Figure 4). The low toxic of compound 3a was also supported by CCK-8 assay.
(Figure S4).
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
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4
5
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5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
0 μM
20 μM
20 μM
Figure 4. Fluorescence images of HeLa cells stained with 10 μmol/L 3a. From left to right
are fluorescence image, bright field image, and overlay image.
Conclusion
In conclusion, we report a novel and efficient radical cascade cyclization strategy, by
which a wide variety of 3-sulfonated indenones were prepared in one-pot via reaction of 2-
alkynylbenzonitriles with sulfonyl hydrazides in the presence of TBHP and CuI under mild
reaction conditions. The cascade reaction is constituted by the selective addition of sulfonyl
radical to the C-C triple bond of 2-alkynylbenzonitriles, intramolecular cyclization and in
situ hydrolysis. Copper catalyst is essential both for the formation of sulfonyl radicals in
the radical initiation steps and for the smooth progress of the radical cascade cyclization
reaction. The mechanism was further supported by DFT calculation. Great advantages of
this strategy include catalytic amount of copper, experimental simplicity and efficiency,
mild reaction conditions and easy work-up. More importantly, the 3-sulfonyl indenones,
synthesized through our newly developed copper-catalyzed radical cascade cyclization
strategy, were found to own typical aggregation-induced emission (AIE) properties,
showing orange to red emission with large stokes shift (more then 135 nm). In addition,
such novel AIEgens could be successfully used in live cell imaging, exhibiting excellent
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biocompatibility and application potential. Further studies on the applications of this
synthetic strategy as well as 3-sulfonated indenones as a new type of AIE fluorescent
material are underway in our laboratory.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
General Information
1
13
19
H, C and F NMR spectra were recorded with a Bruker Avance 400 or 600 MHz
1
3
spectrometer. C NMR spectra being recorded with broad band proton decoupled. Proton
chemical shifts δ were given in ppm using tetramethyl silane as internal standard. All NMR
spectra were recorded in CDCl at room temperature (20 ± 3 °C). High resolution mass
3
spectra (HRMS) were taken with a 3000-mass spectrometer, using Waters Q-Tof MS/MS
system using the ESI technique. For column chromatography, 200-300 mesh silica gel was
used as the stationary phase. Fluorescence spectra were recorded with Hitachi F-4600
spectrophotometer. The bioimaging of Hela cells was measured on the Leica TCS SP8
confocal microscopy system in College of Public Health, Zhengzhou University.
The synthesis of 2-arynylbenzonitrile ： A mixture of 2-bromobenzonitrile or 2-
iodobenzonitrile (1.0 equiv., 10 mmol), alkynes (1.2 equiv., 12.0 mmol), Pd(PPh ) Cl
2
3
2
(
0.02 equiv., 0.2 mmol) and CuI (0.01 equiv., 0.1 mmol) in Et N (40 mL) was stirred at 60
3
ºC under N atmosphere for 2 h. After completion of the reaction as indicated by TLC, the
2
reaction was quenched with aqueous NH Cl and extracted with ethyl acetate (3 × 10 mL).
4
The combined organic layers were washed with water (3 × 10 mL) and brine (1 × 10 mL),
and then dried over anhydrous Na SO . The solvent was removed under reduced pressure
2
4
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and purified by column chromatography (petroleum ether: ethyl acetate = 100:1) to afford
the desired product.
The synthesis of aryl sulfonyl hydrazides：The hydrazine hydrate (40% in water) (23
0
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mmol) was added into the solution of aryl sulfonyl chloride (10 mmol) in THF (50 mL) at
0
ºC. Subsequently, the mixture was stirred at room temperature for 30 minutes. The
solvent was removed by evaporation, and the residue was extracted with dichloromethane.
The organic layer was washed with water, and brine, and dried over Na SO . The organic
2
4
solvent was evaporated under reduced pressure and the residue was purified on silica gel
flash chromatography to give products.
Typical procedure of the CuI-catalyzed radical cascade cyclization: To a 25 mL
reaction tube, 2-(phenylethynyl) benzonitrile (0.2 mmol), sulfonyl hydrazide (0.4 mmol),
CuI (20 mol%), CH CN (1.5 mL), H O (0.5 mL) and TBHP (0.8 mmol) were added. The
3
2
mixture was stirred at 60 ºC for 8 h. After cooling, the solvent was evaporated under
vacuum, and the residue was quenched with water (5 mL), extracted with ethyl acetate (5
mL × 3). The combined organic layers were washed with brine (15 mL) and dried over
anhydrous Na SO . The residue was purified by silica gel chromatography (petroleum
2
4
ether/ethyl acetate = 10/1) to give the desired product.
2-phenyl-3-tosyl-1H-inden-1-one (3a)
1
5
1 mg, 72%; Yellow solid, mp 136-138 °C; H NMR (400 MHz, CDCl , δ) 7.98 (d, J = 7.6
3
Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.56-7.47 (m, 3H), 7.45-7.29 (m, 4H), 7.29-7.19 (m,
1
3
1
2H), 7.14 (d, J = 8.1 Hz, 2H), 2.35 (s, 3H); C{ H} NMR (100 MHz, CDCl , δ) 194.3,
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51.3, 145.2, 141.22, 139.9, 136.8, 135.0, 130.4, 129.6, 129.5, 128.8, 127.9, 127.8, 127.6,
+
24.4, 123.9, 21.6; HRMS Calcd for C H O S [M + H] : m/z 361.0898, Found: 361.0896.
22 17
3
2-(p-tolyl)-3-tosyl-1H-inden-1-one (3b)
6 mg, 76%; Red solid, mp 133-135 °C; H NMR (400 MHz, CDCl , δ) 7.93 (d, J = 7.6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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0
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Hz, 1H), 7.65-7.52 (m, 3H), 7.50-7.46 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.20-7.18 (m, 4H),
1
3
1
7.15 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H), 2.34 (s, 3H); C{ H} NMR (100 MHz, CDCl , δ)
3
1
94.5, 150.5, 145.2, 141.3, 140.2, 139.8, 137.0, 135.0, 130.5, 129.6, 129.3, 128.8, 128.4,
+
127.8, 124.9, 124.3, 123.7, 21.6, 21.5; HRMS Calcd for C H O S [M + H] : m/z 375.1055,
2
3
19
3
Found: 375.1052
2-(m-tolyl)-3-tosyl-1H-inden-1-one (3c)
1
5
4 mg, 73%; Yellow solid, mp 140-143 °C; H NMR (400 MHz, CDCl , δ) 7.97 (d, J = 7.6
3
Hz, 1H), 7.61-7.52 (m, 3H) , 7.49 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.26-7.15
(m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.2Hz, 2H), 6.97 (s, 1H), 2.33 (s, 3H), 2.32
13
1
(s, 3H); C{ H} NMR (100 MHz, CDCl , δ) 194.4, 151.2, 145.2, 141.2, 140.0, 137.1,
3
136.8, 135.0, 130.8, 130.2, 129.56, 129.51, 128.8, 127.9, 127.8, 127.6, 127.4, 124.4, 123.9,
+
2
2
5
1.6, 21.3; HRMS Calcd for C H O S [M + H] : m/z 375.1055, Found: 375.1056
2
3
19
3
-(o-tolyl)-3-tosyl-1H-inden-1-one (3d)
2 mg, 70%; Yellow solid. mp 137-140 °C; H NMR (400 MHz, CDCl , δ) 8.04 (d, J = 7.6
1
3
Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.52-7.55 (m, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.32-7.35
(m, 1H), 7.29-7.25 (m, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.12-7.08 (m, 3H), 7.02-7.00 (m, 1H),
1
3
1
2
.36 (s, 3H), 1.87 (s, 3H) ; C{ H} NMR (100 MHz, CDCl , δ)193.9, 152.8, 145.3, 141.1,
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41.0, 136.8, 136.4, 134.9, 130.1, 129.7, 129.6, 129.5, 129.3, 129.0, 128.1, 125.2, 124.5,
+
23.9, 21.6, 20.2; HRMS Calcd for C H O S [M + H] : m/z 375.1055, Found: 375.1055
23 19
3
-(4-ethylphenyl)-3-tosyl-1H-inden-1-one (3e)
0
1
2
3
4
5
6
7
8
9
0
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2
3
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6
7
8
9
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60 mg, 77%; Red solid, mp 144-146 °C; H NMR (400 MHz, CDCl , δ) 7.95 (d, J = 7.6
3
Hz, 1H), 7.56-7.54 (m, 3H), 7.49 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.21-7.11 (m,
4
3
1
H), 7.12 (d, J = 8.0 Hz, 2H), 2.68 (q, J = 7.6 Hz, 2H), 2.33 (s, 3H), 1.26 (t, J = 7.6 Hz,
1
3
1
H); C{ H} NMR (100 MHz, CDCl , δ) 194.5, 150.6, 146.1, 145.1, 141.3, 140.0, 136.9,
3
35.0, 130.6, 129.5, 129.3, 128.8, 127.9, 127.2, 125.0, 124.3, 123.8, 28.8, 21.6, 15.4;
+
HRMS Calcd for C H O S [M + H] : m/z 389.1211, Found: 389.1208
2
4
21
3
2
-(4-methoxyphenyl)-3-tosyl-1H-inden-1-one (3f)
1
61 mg, 78%; Red solid, mp 131-132 °C; H NMR (400 MHz, CDCl , δ) 7.93 (d, J = 7.6
3
Hz, 1H), 7.58-7.54 (m, 3H), 7.50-7.46 (m, 1H), 7.32-7.26 (m, 3H), 7.16 (d, J = 8.4 Hz,
1
3
1
2H), 6.91 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.35 (s, 3H); C{ H} NMR (100 MHz, CDCl ,
3
δ) 194.7, 161.0, 149.5, 145.1, 141.5, 139.8, 137.1, 135.0, 132.5, 129.6, 129.2, 128.7, 127.7,
+
1
24.3, 123.6, 119.9, 113.2, 55.3, 21.6; HRMS Calcd for C H O S [M + H] : m/z 391.1004,
2
3
19
4
Found:391.1001
2
3
1
-(4-fluorophenyl)-3-tosyl-1H-inden-1-one (3g)
1
9 mg, 52%; Red soild, mp 127-129 °C; H NMR (400 MHz, CDCl , δ) 7.96 (d, J = 7.6 Hz,
3
H), 7.57-7.54 (m, 3H), 7.50 (t, J = 7.6 Hz, 1H), 7.33-7.27 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H),
1
3
1
1
7.08-7.03 (m, 2H), 2.35 (s, 3H); C{ H} NMR (100 MHz, CDCl , δ) 194.1, 163.5 (d, J
=
3
C-F
2
49.2 Hz), 151.3, 145.5, 141.0, 138.8, 136.8, 135.1, 132.7 (d, 3JC-F = 8.4 Hz), 129.7, 129.6,
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28.7, 127.8, 124.5, 123.9, 123.7 (d, 4JC-F = 3.5 Hz), 114.9 (d, 2JC-F= 22.0 Hz) , 21.6; F NMR
19
1
+
(
376 MHz, CDCl , δ) -110.4; HRMS Calcd for C H FO S [M + H] : m/z 379.0804, Found:
3
22 16
3
3
79.0801
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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2
2
3
3
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2-(4-chlorophenyl)-3-tosyl-1H-inden-1-one (3h)
1
4
1
5 mg, 58%, Red solid, mp 130-131 °C; H NMR (400 MHz, CDCl , δ) 7.95 (d, J = 7.2 Hz,
3
H), 7.57 (d, J = 8.4 Hz, 3H), 7.52-7.49 (m, 1H), 7.35-7.30 (m, 3H), 7.23-7.17 (m, 4H), 2.37
1
3
1
(
s, 3H); C{ H} NMR (100 MHz, CDCl , δ) 193.9, 151.6, 145.6, 140.9, 138.5, 136.7, 135.9,
3
1
35.1, 131.9, 129.8, 129.7, 128.7, 127.9, 126.2, 124.5, 124.0, 21.6; HRMS Calcd for
+
C H ClO S [M + H] : m/z 395.0509, Found: 395.0507
2
2
16
3
2
-(4-bromophenyl)-3-tosyl-1H-inden-1-one (3i)
1
57 mg, 65%; Red solid. mp 132-133 °C; H NMR (400 MHz, CDCl , δ) 7.95 (d, J = 7.2 Hz,
3
1
H), 7.58-7.55 (m, 3H), 7.55-7.48 (m, 3H), 7.35-7.31 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H),
1
3
1
7.16-7.12 (m, 2H), 2.37 (s, 3H); C{ H} NMR (100 MHz, CDCl , δ) 193.8, 151.6, 145.6,
3
1
1
40.9, 138.5, 136.6, 135.1, 132.1, 130.9, 129.8, 129.7, 128.7, 127.9, 126.7, 124.5, 124.3,
+
24.0, 21.7; HRMS Calcd for C H BrO S [M + H] : m/z 439.0004, Found:439.0000
2
2
16
3
2
-(pyren-1-yl)-3-tosyl-1H-inden-1-one (3j)
1
3
3 mg, 34%; Brown solid. mp 183-184 °C; H NMR (400 MHz, CDCl , δ) 8.22 (d, J = 7.6
3
Hz, 1H), 8.16 (d, J = 7.2 Hz, 2H), 8.12-8.07 (m, 2H), 8.05-8.00 (m, 2H), 7.89 (d, J = 9.2
Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.63-7.59 (m, 1H), 7.47-7.40
1
3
1
(m, 2H), 7.16 (d, J = 8.4Hz, 2H), 6.31(d, J = 8.4Hz, 2H), 1.46 (s, 3H); C{ H} NMR (100
MHz, CDCl , δ) 194.4, 154.8, 144.7, 141.1, 138.8, 135.1, 131.9, 131.0, 130.7, 129.8, 129.5,
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29.0, 128.5, 128.2, 128.0, 127.8, 127.7, 127.1, 126.1, 125.7, 125.5, 124.8, 124.6, 124.28,
+
1
24.2, 124.1, 124.0, 123.1, 20.6; HRMS Calcd for C H O S [M + H] : m/z 485.1211,
32 21
3
Found: 485.1205
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
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1
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6-methyl-2-phenyl-3-tosyl-1H-inden-1-one (3k)
1
4
8 mg, 65%; Yellow solid. mp 165-167 °C; H NMR (400 MHz, CDCl , δ) 7.83 (d, J = 7.6
3
Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.41-7.33 (m, 4H), 7.29-7.23 (m, 3H), 7.13 (d, J = 8.0
1
3
1
Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H); C{ H} NMR (100 MHz, CDCl , δ) 194.6, 153.1,
3
1
51.5, 145.1, 140.0, 139.3, 138.4, 136.9, 135.0, 130.4, 129.6, 129.3, 129.1, 128.0, 127.8,
+
127.6, 125.4, 123.7, 21.6, 21.2; HRMS Calcd for C H O S [M + H] : m/z 375.1055,
2
3
19
3
Found: 375.1054
6-chloro-2-phenyl-3-tosyl-1H-inden-1-one (3l)
1
5
8 mg, 74%; Yellow solid. mp 158-160 °C; H NMR (400 MHz, CDCl , δ) 7.93 (d, J = 8.0
3
Hz, 1H), 7.51-7.45 (m, 4H), 7.43-7.33 (m, 3H), 7.25-7.23 (m, 2H), 7.12 (d, J = 8.0 Hz,
1
3
1
2
1
H), 2.34 (s, 3H); C{ H} NMR (100 MHz, CDCl , δ) 193.1, 151.2, 145.5, 139.8, 139.2,
3
36.5, 135.9, 134.2, 130.47, 130.40, 129.74, 129.70, 127.9, 127.7, 127. 4, 124.9, 124.8,
+
21.6; HRMS Calcd for C H ClO S [M + H] : m/z 395.0509, Found: 395.0504
2
2
16
3
6
-bromo-2-phenyl-3-tosyl-1H-inden-1-one (3m)
1
6
7 mg, 73%; Yellow solid. mp 163-165 °C; H NMR (400 MHz, CDCl , δ) 7.87 (d, J = 7.6
3
Hz, 1H), 7.66-7.63 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.41-7.33 (m, 3H), 7.25-7.23 (m,
1
3
1
2H), 7.12 (d, J = 7.6 Hz, 2H), 2.34 (s, 3H); C{ H} NMR (100 MHz, CDCl , δ) 193.1,
3
1
51.3, 145.5, 139.8, 139.6, 137.3, 136.6, 130.4, 129.75, 129.70, 127.8, 127.7, 127.6, 127.
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+
4
4
, 125.2, 123.7, 21.6; HRMS Calcd for C H BrO SNa [M + Na] : m/z 460.9823, Found:
22 15 3
60.9819
7-fluoro-2-phenyl-3-tosyl-1H-inden-1-one (3n)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
8 mg, 77%; Yellow solid. mp 156-158 °C; H NMR (400 MHz, CDCl , δ) 7.83 (d, J = 7.6
3
Hz, 1H), 7.53-7.47 (m, 3H), 7.39 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.2 Hz, 2H), 7.24 (d, J =
1
3
1
7.2 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.97 (t, J = 8.4 Hz, 2H), 2.32 (s, 3H); C{ H} NMR
100 MHz, CDCl , δ) 190.1 (d, J = 1.4 Hz), 158.4 (d, 1JC-F = 265.2 Hz), 150.5 (d, 4JC-F
3
(
3
C-F
= 4.3 Hz), 145.4, 142.7 (d, 3JC-F = 3.3 Hz), 140.7, 137.6 (d, 3JC-F = 8.6 Hz), 136.6, 130.5,
1
1
29.74, 129.71, 127.8, 127.6, 127.4, 120.3 (d, 4JC-F = 2.3 Hz), 118.8 (d, 2JC-F = 20.9 Hz),
14.4 (d, 2JC-F = 13.1 Hz), 21.6; F NMR (376 MHz, CDCl , δ) -110.3; HRMS Calcd for
19
3
+
C H FO S [M + H] : m/z 379.0804, Found: 379.0804
2
2
16
3
2
-phenyl-3-(phenylsulfonyl)-1H-inden-1-one (3o)
1
4
4 mg, 63%; Yellow solid. mp 130-132 °C; H NMR (400 MHz, CDCl , δ) 8.00 (d, J = 7.6
3
Hz, 1H), 7.65 (dd, J = 1.2 Hz, J = 8.4 Hz, 2H), 7.59 (d, J = 7.2 Hz, 1H), 7.54-7.48 (m,
1
2
1
3
1
2H), 7.40-7.31 (m, 6H), 7.26-7.23 (m, 2H); C{ H} NMR (100 MHz, CDCl , δ) 194.1,
3
1
51.0, 141.1, 140.3, 139.8, 135.1, 134.0, 130.4, 129.65, 129.60, 128.9, 128.7, 127.79,
+
1
27.75, 127.70, 124.5, 123.9; HRMS Calcd for C H O S [M + H] : m/z 347.0742,
21 15 3
Found:347.0740
2-phenyl-3-(m-tolylsulfonyl)-1H-inden-1-one (3p)
1
4
7 mg, Yellow solid. mp 133-135 °C; H NMR (400 MHz, CDCl , δ) 8.01 (d, J = 6.8 Hz,
3
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
1
H), 7.56-7.46 (m, 3H), 7.36-7.22 (m, 9H), 2.23 (s, 3H); C{ H} NMR (100 MHz, CDCl ,
3
δ) 194.2, 151.4, 141.2, 140.1, 139.5, 139.2, 135.1, 134.8, 130.4, 129.5, 128.8, 128.7, 128.3,
+
1
27.8, 127.6, 124.9, 124.4, 124.0, 21.1; HRMS Calcd for C H O S [M + H] : m/z
2
2
17
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
361.0898, Found: 361.0855
2
-phenyl-3-(o-tolylsulfonyl)-1H-inden-1-one (3q)
1
48 mg, 67%; Yellow solid. mp 132-134 °C; H NMR (400 MHz, CDCl , δ) 7.91 (d, J = 7.6
3
Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.50-7.46 (m, 1H), 7.34-7.24
1
3
1
(m, 3H), 7.22-7.15 (m, 4H), 7.06 (t, J = 8.4 Hz, 2H), 2.39 (s, 3H) ; C{ H} NMR (100
MHz, CDCl , δ) 194.2, 150.7, 141.3, 139.0, 138.0, 137.3, 135.1, 133.8, 132.2, 130.2, 129.6,
3
1
29.5, 128.5, 127.5, 127.3, 125.9, 124.4, 124.1, 20.1; HRMS Calcd for C H O S [M +
22 17 3
+
H] : m/z 361.0898, Found: 361.0897
3
-((4-methoxyphenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3r)
1
5
6 mg, 74%; Yellow solid. mp 136-138 °C; H NMR (400 MHz, CDCl , δ) 7.99 (d, J = 7.6
3
Hz, 1H), 7.58-7.55 (m, 3H), 7.51 (t, J = 7.6 Hz, 1H), 7.42-7.30 (m, 4H), 7.25-7.23 (m, 2H),
1
3
1
6.79-6.77 (m, 2H), 3.79 (s, 3H) ; C{ H} NMR (100 MHz, CDCl , δ) 194.3, 164.0, 151.7,
3
1
1
41.2, 139.5, 135.0, 131.2, 130.4, 130.2, 129.5, 129.4, 128.8, 127.9, 127.6, 124.3, 123.9,
+
14.2, 55.6; HRMS Calcd for C H O S [M + H] : m/z 377.0848, Found: 377.0844
2
2
17
4
3
-((4-(tert-butyl)phenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3s)
1
60 mg, 75%; Red solid. mp 165-168 °C; H NMR (400 MHz, CDCl , δ) 8.01 (d, J = 7.6
3
Hz, 1H), 7.66-7.58 (m, 3H), 7.54-7.49 (m, 1H), 7.37-7.29 (m, 6H), 7.23-7.20 (m, 2H), 1.26
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(
s, 9H) ; C{ H} NMR (100 MHz, CDCl , δ) 194.3, 158.0, 151.4, 141.2, 139.7, 136.5,
3
1
35.0, 130.4, 129.5, 129.4, 128.79, 127.88, 127.83, 127.6, 125.9, 124.4, 124.0, 35.2, 30.9;
+
HRMS Calcd for C H O S [M + H] : m/z 403.1368, Found: 403.1366
2
5
23
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
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4
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
-((4-fluorophenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3t)
1
4
2 mg, 58%; Yellow solid. mp 135-137 °C; H NMR (400 MHz, CDCl , δ) 8.01 (d, J = 7.6
3
Hz, 1H), 7.65-7.59 (m, 3H), 7.55-7.51 (m, 1H), 7.43-7.33 (m, 4H), 7.23-7.21 (m, 2H), 7.00-
1
3
1
1
6
.95 (m, 2H); C{ H} NMR (100 MHz, CDCl , δ) 193.9, 165.8 (d, J = 256.2 Hz), 151.1,
3 C-F
141.0, 140.1, 135.7 (d, 4JC-F = 2.9 Hz), 135.1, 130.8 (d, 3JC-F = 9.6 Hz), 130.4, 129.74,
29.72, 128.6, 127.79, 127.70, 124.6, 123.9, 116.2 (d, 2JC-F = 22.7 Hz); F NMR (376 MHz,
19
1
+
CDCl , δ) -102.2; HRMS Calcd for C H FO S [M + H] : m/z 365.0648, Found: 365.0646
3
21 14
3
3
-((4-chlorophenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3u)
1
4
8 mg, 63%; Yellow solid. mp 136-139 °C; H NMR (400 MHz, CDCl , δ) 7.99 (d, J = 7.6
3
Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.56-7.50 (m, 3H), 7.44-7.40 (m, 1H), 7.37-7.32 (m,
13
1
3
H), 7.29-7.25 (m, 2H), 7.23-7.21 (m, 2H) ; C{ H} NMR (100 MHz, CDCl , δ) 193.9,
3
150.8, 140.9, 140.8, 140.3, 138.1, 135.2, 130.4, 129.79, 129.76, 129.27, 129.24, 128.65,
+
1
3
27.8, 127.6, 124.6, 123.9; HRMS Calcd for C H ClO S [M + H] : m/z 381.0352, Found:
2
1
14
3
81.0350
3
-((4-bromophenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3v)
1
57 mg, 68%; Yellow solid. mp 140-141 °C; H NMR (400 MHz, CDCl , δ) 7.98 (d, J = 7.2
3
Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.48-7.40 (m, 5H), 7.37-7.32 (m,
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2
2
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5
5
5
5
5
5
5
6
13
1
3
1
H), 7.22-7.20 (m, 2H); C{ H} NMR (100 MHz, CDCl , δ) 193.9, 150.8, 140.9, 140.3,
3
38.6, 135.2, 132.2, 130.4, 129.79, 129.77, 129.5, 129.2, 128.6, 127.8, 127.6, 124.6, 123.9;
+
HRMS Calcd for C H BrO S [M + H] : m/z 424.9847, Found: 424.9845
2
1
14
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
-((4-iodophenyl)sulfonyl)-2-phenyl-1H-inden-1-one (3w)
1
6
6 mg, 70%; Red solid. mp 143-145 °C; H NMR (400 MHz, CDCl , δ) 7.98 (d, J = 7.6
3
Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.54-7.50 (m, 1H), 7.45-7.41
1
3
1
(
m, 1H), 7.38-7.30 (m, 5H), 7.22-7.20 (m, 2H); C{ H} NMR (100 MHz, CDCl , δ) 193.9,
3
150.8, 140.9, 140.3, 139.3, 138.2, 135.2, 130.4, 129.7, 129.0, 128.6, 127.8, 127.6, 124.6,
+
1
23.9, 102.3; HRMS Calcd for C H IO S [M + H] : m/z 472.9708, Found: 472.9705
2
1
14
3
2-phenyl-3-((4-(trifluoromethyl)phenyl)sulfonyl)-1H-inden-1-one (3x)
1
3
7 mg, 43%; Yellow solid. mp 162-166 °C; H NMR (400 MHz, CDCl , δ) 8.02 (d, J = 7.6
3
Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.56-7.52 (m, 3H), 7.42-7.30
1
3
1
(
m, 4H), 7.19 (d, J = 7.2 Hz, 2H); C{ H} NMR (151 MHz, CDCl , δ) 193.6, 150.5, 143.1,
3
1
40.9, 140.7, 135.4 (q, 2JC-F = 33.1 Hz ), 135.2, 130.4, 129.88, 129.86, 128.6, 128.4, 127.8,
127.5, 125.9 (q, 3JC-F = 3.7 Hz), 124.8, 124.0, 122.9 (q, 1JC-F = 273.3 Hz) ; F NMR (376
19
+
MHz, CDCl , δ) -63.3; HRMS Calcd for C H F O S [M + H] : m/z 415.0616, Found:
3
22 14
3
3
4
15.0599
2
,6-di-tert-butyl-4-(tosylmethyl)phenol (9)
1
White solid, mp 131-133 °C; H NMR (400 MHz, CDCl , δ) 7.46 (d, J = 8.4 Hz, 2 H), 7.24
3
1
3
1
(d, J = 8.0 Hz, 2 H), 6.8 (s, 2 H), 5.3 (s, 1 H), 4.2 (s, 2 H), 2.4 (s, 3 H), 1.3 (s,18 H). C{ H}
NMR (101 MHz, CDCl , δ) 154.2, 144.3, 135.9, 134.8, 129.3, 128.9, 127.6, 118.9, 63.2,
3
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4.1, 30.0, 21.5.
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.xxxxxxx
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19
H, C, F NMR spectra and HRMS date for all products, The density functional theory
(DFT) data, primary mechanistic studies of the reactions (PDF)
X-ray data for 3a (CIF)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We acknowledge financial support from National Natural Science Foundation of China
(
Nos. 21501010, 21708035), the 2017 Science and Technology Innovation Team in Henan
Province (No. 22120001), Major scientific and technological projects in Henan Province
No. 181100310500), China Postdoctoral Science Foundation (No. 2017M620302), and
the Key Laboratory for Chemical Biology of Fujian Province (Xiamen University) (No.
017002)
(
2
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