Air-stable μ-oxo-bridged binuclear titanium(IV) salophen perfluorooctanesulfonate as a highly efficient and recyclable catalyst for the synthesis of bis(indolyl) methane derivatives

Article abstract of DOI:10.1016/j.jorganchem.2019.121039

An air-stable μ-oxo-bridged binuclear Lewis acid of titanium(IV) salophen perfluorooctanesulfonate [{Ti(salophen)H₂O}₂O][OSO₂C₈F₁₇]₂ (1) was successfully synthesized by the reaction of Ti^IV(salophen)Cl₂ with AgOSO₂C₈F₁₇ and characterized by different techniques such as IR, NMR and HRMS. TG-DSC analysis showed that this complex was thermally stable at 220 °C. Meanwhile, it exhibited good solubility in polar organic solvents and good ionic dissociation in CH₃CN solution. Fluorescence spectra and Hammett indicator results indicated that the complex had relatively strong acidity. And it showed high catalytic efficiency for the synthesis of bis(indolyl) methane derivatives through Friedel-crafts reaction of aldehyde/ketone with indoles. Moreover, it can be reused five times with minimal changes in catalytic efficiency.

Full text of DOI:10.1016/j.jorganchem.2019.121039

Journal Pre-proof
Air-stable μ-oxo-bridged binuclear titanium(IV) salophen perfluorooctanesulfonate
as a highly efficient and recyclable catalyst for the synthesis of bis(indolyl) methane
derivatives
Jie Qiao, Shan Gao, Lingxiao Wang, Jiancong Wei, Ningbo Li, Xinhua Xu
PII:
S0022-328X(19)30482-6
DOI:
https://doi.org/10.1016/j.jorganchem.2019.121039
JOM 121039
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 17 August 2019
Revised Date: 26 October 2019
Accepted Date: 20 November 2019
Please cite this article as: J. Qiao, S. Gao, L. Wang, J. Wei, N. Li, X. Xu, Air-stable μ-oxo-bridged
binuclear titanium(IV) salophen perfluorooctanesulfonate as a highly efficient and recyclable catalyst
for the synthesis of bis(indolyl) methane derivatives, Journal of Organometallic Chemistry (2019), doi:
https://doi.org/10.1016/j.jorganchem.2019.121039.
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Air-stable µ-oxo-bridged binuclear titanium(IV) salophen
perfluorooctanesulfonate as a highly efficient and recyclable catalyst for
the synthesis of bis(indolyl) methane derivatives
Jie Qiaoa,b, Shan Gaoa, Lingxiao Wangb, Jiancong Weib, , Ningbo Lia,b, and Xinhua
Xuc
a Department of Biochemistry and Molecular Biology, Basic Medical College, Shanxi Medical University, Taiyuan
030001, China
b Department of Chemistry, Basic Medical College, Shanxi Medical University, Taiyuan 030001, China
c College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
Abstract
An air-stable µ-oxo-bridged binuclear Lewis acid of titanium(IV) salophen
perfluorooctanesulfonate [{Ti(salophen)H2O}2O][OSO2C8F17]2 (1) was successfully synthesized
by the reaction of TiIV(salophen)Cl2 with AgOSO2C8F17 and characterized by different techniques
such as IR, NMR and HRMS. TG-DSC analysis showed that this complex was thermally stable at
220 °C. Meanwhile, it exhibited good solubility in polar organic solvents and good ionic
dissociation in CH3CN solution. Fluorescence spectra and Hammett indicator results indicated that
the complex had relatively strong acidity. And it showed high catalytic efficiency for the synthesis
of bis(indolyl) methane derivatives through Friedel-crafts reaction of aldehyde/ketone with indoles.
Moreover, it can be reused five times with minimal changes in catalytic efficiency.
Keywords: TiIV(salophen) complex; Perfluorooctanesulfonate; Friedel-crafts reaction; Bis(indolyl)
methanes; Recyclability.
Corresponding author.
E-mail address: jiancongwei@sxmu.edu.cn
Corresponding author.
E-mail address:ningboli@sxmu.edu.cn; Tel./Fax: (+ 86) 351 3985152
1

1. Introduction
Bis(indolyl)methane derivatives have been often encountered as an important framework and
intermediate in pharmaceuticals and agrochemicals, organic synthesis and materials science [1].
Various drugs and biological molecules such as anticancer agent, arsindoline A and anti-infective
agent contain bis(indolyl)methane in their backbone [2,3] (Fig. 1). Based on their wide
applications, novel strategies for the synthesis of bis(indolyl)methane derivatives are vital
important to be developed.
Fig. 1 Biological molecules containing bis(indolyl)methanes.
At present, one of the most convenient routes for the synthesis of bis(indolyl)methanes is
through the Friedel-Crafts alkylation of aldehyde/ketone with indoles in the presence of either
protic acid or Lewis acid. Those reported catalysts including H3PW12O40 [4], silica supported
sulfuric acid [5], itaconic acid [6], InCl3 [7], FeCl3 [8], LiClO4 [9], SbCl3 [10], ZrOCl2 [11],
La(NO3)·6H2O [12], CAN [13], Dy(OTf)3 [14], Ln(OTf)3 [15], Yb(OTf)3/SDS[16],
Zr(Salophen)Cl2 [17], I2 [18], Br2 [19], ionic liquid [20], et.al. Nonetheless, above reported
methods for bis(indolyl)methanes synthesis suffer from certain drawbacks, e.g., the use of air or
moisture-sensitive catalysts, requiring strict anhydrous conditions, the need for large catalytic dose,
low yield, functional group intolerance, poor reusability. Although rare-earth metal triflates can
effectively catalyze the reaction, their high prices limit the further utilization. Therefore, the
2

development of an air-stable and highly efficient and recyclable catalyst for the synthesis of
bis(indolyl) methanes is still worthwhile.
Organometallic Lewis acids-catalyzed carbonyl group transformation is of great significance
in organometallic chemistry and catalysis [21,22]. Among them, group 4 metal compounds drawn
considerable attention owing to their highly catalytic activity and facile availability [23-25]. For
example, titanium Schiff base complexes have been used as catalysts for olefin polymerization
[26], ring-opening of epoxides [27], trimethylsilylcyanation or acetylation of alcohols and phenols
[28,29]. However, titanium Schiff base complexes have rarely been reported as Lewis acid catalyst.
The reason may be that the ligand containing N and O atoms reduces the Lewis acidity of titanium
compounds. In order to increase the Lewis acidity of the titanium schiff base complexes, the direct
method is to introduce electron-withdrawing group(s) into titanium [30]. In recent years, our
group has reported
a
series of air-stable metallocene and organoantimony
perfluoroalkyl(aryl)sulfonate complexes, which showed strong Lewis acidity and high catalytic
activity in many organic reactions [31-37]. The above results indicate that
perfluoroalkyl(aryl)sulfonate groups can be used as effective counter anions to increase the acidity
as well as the water tolerance [38,39]. With this in mind, we envisioned that a
perfluorooctanesulfonate group introduced into the titanium salophen compound by the
replacement of a chlorine atom might enhance the acidity of the complex. In this study, an
air-stable
µ-oxo-bridged
binuclear
titanium(IV)
salophen
perfluorooctanesulfonate
[{Ti(salophen)H2O}2O][OSO2C8F17]2 (1) was successfully synthesized and characterized.
Furthermore, we report a mild and efficient protocol for synthesis of bis(indolyl) methanes
3

through the Friedel-Crafts alkylation of aldehyde/ketone with indoles catalyzed by complex 1 at
room temperature (Scheme 1).
Scheme 1 The synthesis of bis(indolyl) methanes
2. Experimental
All chemicals were purchased from Aladdin reagent Co. and used as received unless otherwise
indicated. IR spectra were recorded on a NICOLET 6700 FTR spectrophotometer (Thermo
Electron Corporation). NMR spectra were recorded at 25
on a INOVA-400Mcalibrated with
tetramethylsilane (TMS) as the internal reference (USA). High resolution mass spectra were
recorded using a Thermo Scientific Q Exactive in Shanxi University. TG-DSC analysis was
performed using a HCT-1 (HENVEN, Beijing, China) instrument. Conductivity was measured on
a REX conductivity meter DDS-307. Fluorescence spectroscopy was tested on a HITACHIF-4600
instrument in Hunan Unversity. The acidity was measured by the Hammett indicator method as
described previously. Acid strength was expressed in terms of Hammett acidity function (Ho) as
scaled by the pKa value of the indicators. The starting material TiIV(salophen)Cl2 was prepared
according to the literature [40].
2.1 Preparation of [{Ti(salophen)H2O}2O][OSO2C8F17]2 (1)
A THF solution (10 mL) of AgOSO2C8F17 (1.21 g, 2 mmol) was added to a solution of
[TiIV(salophen)Cl2] (0.432 g, 1 mmol) in THF (10 mL), After the mixture was stirred at room
temperature for 2 h in the absence of light. A brown precipitate was produced. The AgCl that
formed was filtered off through a fine fritted funnel. The filtrate was placed in a small jar, which
was put into a larger jar containing dry hexane (20 mL). The larger jar was sealed and refrigerated
for 24 h. Red solid of complex 1 were obtained (1.383 g, 78% yield of the isolated product).
1H NMR (400 MHz, [D6]acetone) δ: 9.13 (s, 4H, H-C=N), 7.84-7.82 (m, 4H, Ar), 7.76 (d, 4H, J
= 7.2 Hz, Ar), 7.53 (t, 4H, J = 6.8 Hz, Ar), 7.37-7.35 (m, 4H, Ar), 7.00 (t, 4H, J = 7.2 Hz, Ar),
4

6.56 (d, 4H, J = 8.0 Hz, Ar), 3.71 (s, 4H; H2O); 19F NMR (376 MHz, [D6]acetone): δ: -126.66 to
-126.74 (m, 2F; -CF2-), -123.24 (s, 2F; -CF2-), -122.09 to -122.40 (d, 6F; -(CF2)3-), -121.02 (s, 2F;
-CF2-), -115.11 to -115.19 (m, 2F; -CF2-), -81.62 to -81.67 ppm (m, 3F; CF3-); IR(KBr): ν = 3469,
2923, 2856, 1605, 1554, 1254, 1148, 1052, 820, 752, 703, 647 cm-1; ESI-HRMS calcd for
C57H37F34N4O14S2Ti2 [1 + CH3OH + H]+: 1807.0158; Found: 1807.1079.
2.2 General Procedure for Synthesis of bis(indolyl) methanes:
A mixture of carbonyl compound (1 mmol), indole (0.234 g, 2 mmol) and 1 (17.7 mg, 1
mmol%) in THF (0.5 mL) was stirred at room temperature for the appropriate reaction time under
the TLC analysis until indole was consumed completely. Then the solvents of the resulted mixture
were removed by evaporation in vacuum, and the residue was dissolved in diethyl ether (30 mL)
followed by filtration. After the catalyst was washed three times with diethyl ether (10 × 3 mL),
and the catalyst was used for catalyzing the next cycle of reaction (the recovered catalyst should
be dried in a vacuum oven at 60 oC for 2 hours). To the filtrate, after evaporation of the solvent a
dark grayish solid mixture was obtained. Purification of the product was performed by a short
column chromatography eluted with ethyl acetate/petroleum ether (1:3) to give the desired
product.
3. Results and discussion
3.1 Preparation, characterization and physiochemical property of complex 1
The synthesis of the titanium salophen compound [{Ti(salophen)H2O}2O][OSO2C8F17]2 (1) is
straightforward by treating TiIV(salophen)Cl2 with AgOSO2C8F17 in THF in the absence of light
for 2 h, and the yield was 78%. Although we tried many ways to obtain single crystals of complex
1, we failed to generate suitable crystals of 1, possibly because of the randomness of the
1
long-chain perfluoroctanesulfonate group. However, all results of IR, HNMR, 19FNMR and
HRMS studies indicate that complex 1 is µ-oxo-bridged binuclear structure and contains two
coordinated water molecules (see ESI), which is different with the complex TiIV(salophen)(OTf)2
reported by Moghadam et.al. [30]. This binuclear structure is similar to our reported
organoantimony complex [34]. We found that complex 1 had excellent air-stability and could be
stored open to air for one year.
5

Scheme 2 The synthetic route of complex 1
The thermal behavior of complex 1 was investigated by TG-DSC in air and in N2 atmosphere
(Fig. 2). The TG-DSC curves showed three stages of weight loss. The endothermic step below
100˚C was assigned to the removal of water molecules. Complex 1 was thermally stable up to
approximately 220 ˚C. Further increasing temperature caused an exothermic weight loss, likely
because of oxidation of organic entities together with the release of heat. At 400˚C, we observed
the removal of perfluorooctanesulfuryl group, leaving titanium fluoride behind.
Fig. 2 The TG-DSC curves of complex 1 in performed in air (left) and N2 (right).
Meanwhile, we estimated the Lewis acidity of complex 1 by the red shift (λem) of Lewis acid
metal ions (Ti2+) with 10-methylacridone based on fluorescence spectra [41], which showed that
the fluorescence maximum (λmax) of complex was 504 nm (Fig. 3), indicating it was relatively
strongly acidic [35]. In addition, the acidity measurement by the Hammett indicator method
showed the acid strength to be 0.8 < H0 ≤ 3.3 (Ho being the Hammett acidity function) [42]. We
also investigated its conductivity, and the molar conductivity (L) of 1 was 136 µScm-1 in CH3CN
o
(1.0 mmol L-1) at 25 C, implying that it is cationic in solution. Subsequently, the solubility of 1
was evaluated. The results showed complex 1 had good solubility in acetone, THF, MeOH,
CH3CN. But it is not soluble in Et2O, CH2Cl2 and toluene. On the basis of above characteristics,
6

we used it as a Lewis catalyst for the synthesis of bis(indolyl) methanes via the Friedel-Crafts
alkylation of aldehyde/ketone with indoles.
Fig. 3 The fluorescence spectrum between 10-methylacridone and complex 1
3.2. Screening optimal conditions
Initial efforts were focused on the optimization of conditions through variation of reaction
parameters using the reaction of indole with benzaldehyde as the model reaction (Table 1).
Controlled experiments showed that no target product was obtained in the absence of complex 1
(entry 1). We investigated the loadings of complex 1 and found that the optimal dosage of
complex 1 was only 1 mol% using THF as solvent for 10 min, and the yield was up to 97%
(entries 2–5). When other solvents, such as CH3OH, CH3CN, Et2O, CH2Cl2, H2O, n-hexane and
toluene were used instead of THF, the reaction gave moderate or low yields (entries 6–12). The
reaction was also performed under solvent-free conditions; however, a moderate yield was
obtained (entry 13). Thus, the best yield was obtained in the presence of complex 1 (1 mol%)
affording the desired 4a in THF after 10 min at room temperature.
Table 1. Optimization of reaction conditions a
Entry
Solvent
THF
Catalyst (mol%)
Time (min/h)
12 h
Yield (%) b
1
2
3
-
0.5
1
0
THF
1 h
72
97
THF
10 min
7

4
5
THF
THF
1
2
1
1
1
1
1
1
1
1
20 min
10 min
1 h
97
96
80
83
60
56
43
59
53
82
6
CH2OH
CH3CN
Et2O
7
1 h
8
1 h
9
CH2Cl2
H2O
3 h
10
11
12
13
3 h
n-hexane
toluene
neat
3 h
3 h
20 min
a PhCHO: 0.5 mmol; indole: 1.0 mmol; THF: 0.5 mL; r.t.; b isolate yield.
3.3 The scope of Friedel-Crafts alkylation catalyzed by complex 1
To demonstrate the efficiency of the Friedel-Crafts alkylation, we explored the generality of
our method by extending the optimal conditions to various substituted indoles and
aldehydes/ketones, and the results were summarized in Table 2. A variety of aromatic aldehydes
could efficiently undergo Friedel-Crafts alkylation to afford the corresponding products in good to
excellent yields (4a-4h, 89-99%). Electron-donating groups (eg. Me, OH) or electron-withdrawing
groups (eg. CF3, Br, Cl and NO2) in the benzene ring affected the reaction slightly. As for
aliphatic aldehyde, a 92% yield of product was obtained (4i). The ketones such as acetophenone
and cyclohexanone also showed good reactive activity in this catalytic system (4j, 4k). Meanwhile,
we also investigated different substituent indoles. The results indicated that indoles with
electron-donating groups (CH3) exhibited slightly higher reactivity than that with
electron-withdrawing groups (F, Cl, Br) in the indole ring (4l-4q). Surprisingly, 1-methylindole
also reacted with benzaldehyde in high yields (4r). Moreover, we synthesized two bioactive indole
derivatives by the reaction of indole-3-carbaldehyde and 4-quinolinecarboxaldehyde with indole,
and satisfactory yields were obtained (4s, 4t).
Table 2. Friedel-Crafts alkylation of indoles with aldehydes/ketones catalyzed by complex 1 a,b
8

CF3
NO2
NH
F3C
HN
NH
HN
NH
HN
NH
HN
4b, 10 min, 98%
4c, 10 min, 94%
4d, 10 min, 99%
4a, 10 min, 97%
Br
Cl
CH3
OH
NH
NH
4f, 15 min, 96%
HN
NH
HN
HN
NH
HN
4e, 15 min, 97%
4g, 30 min, 91%
4h, 40 min, 89%
F
F
NH
HN
NH
HN
4i,
NH
HN
NH
, 12 h, 87%
HN
4j
4k
, 12 h, 85%
4l, 30 min, 86%
50 min, 92%
Br
Br
Cl
Cl
NH
4n, 30 min, 90%
NH
HN
HN
NH
HN
NH
HN
4p, 25 min, 93%
4o, 25 min, 92%
4m, 30 min, 89%
N
HN
N
N
NH
4q, 25 min, 94%
HN
NH
HN
NH
4s, 1 h, 90%
HN
4t
, 1 h, 88%
4r, 30 min, 92%
a aldehydes/ketones: 0.5 mmol; indoles: 1.0 mmol; 1: 0.01mmol; THF: 0.5 mL; r.t.; b isolate yield.
3.4 Comparison of complex 1 with other catalytic systems
In addition, the merits of complex 1 were compared with other titanium compounds and
those of reported catalytic systems for synthesis of bis(indolyl) methanes. Firstly, the activities of
titanium compounds, such as TiIV(salophen)Cl2, Cp2TiCl2, TiIV(salophen)(OTf)2 together with
complex 1 were estimated by the reaction of indole and benzaldehyde in THF at the temperature
(Table 3). Higher yield was obtained over complex 1, while catalysts such as titanium salophen
dichloride and Cp2TiCl2 showed much lower yields, plausibly due to their lower Lewis acidity or
moisture-sensitive properties. Although titanium salophen triflates showed good catalytic activity,
the catalytic efficiency of complex 1 was better, because of the synergetic effect of bimetallic
9

complex 1. Compared to other catalytic systems [9, 11, 14, 16, 17, 19, 20, 43], these results
implied the advantages of this protocol are: a) low catalyst loading, b) short reaction time c) mild
reaction conditions d) and high efficiency. Although the catalyst such as Zr(salophen)Cl2 also
showed some advantages, it can't be recycled [17].
Table 3. Catalyst comparison of titanocene compounds and other catalytic systems for synthesis
of bis(indolyl) methanes a
Entry
Catalyst (mol%)
TiIV(salophen)Cl2 (1 mol%)
Cp2TiCl2 (1 mol%)
Conditions
THF, r.t.
Time(h)
10 min
10 min
10 min
10 min
2 h
Yield /(%)b
Ref.
-
1
10
69
89
97
84
90
88
90
95
95
98
96
90
2
THF, r.t.
-
3
TiIV(salophen)(OTf)2 (1 mol%)
[{Ti(salophen)H2O}2O][OSO2C8F17]2 (1 mol%)
H3PW12O40 (12 mol%)
THF, r.t.
-
THF, r.t.
4
-
5
Neat, r.t.
-
6
LiClO4 (10 mol%)
CH3CN, r.t.
CH3CN, r.t.
EtOH, r.t.
H2O, r.t.
5 h
[9]
[11]
[14]
[16]
[17]
[19]
[20]
[43]
7
ZrOCl2·8H2O (10 mol%)
Dy(OTf)3 (10 mol%)
35 min
12 h
8
9
Yb(OTf)3(5 mol%)/SDS(15 mol%)
Zr(Salophen)Cl2 (1 mol%)
Br2 (2 mol%)
1 h
10
11
12
13
EtOH, r.t.
CH3CN, 50 oC
Neat, r.t.
10 min
1 min
40 min
2 h
TMG IL (3 mol%)
BF3·Et2O (15 mol%)
Et2O, r.t.
a PhCHO: 0.5 mmol; indole: 1.0 mmol; b isolate yield.
3.5 Catalyst recovery investigation
The reusability of complex 1 was also examined when indole was reacted with benzaldehyde.
After the reaction finished and solvent evaporation, the residue was dissolved in diethyl ether, and
the catalyst could be separated by using simple filtration, diethyl ether washing, and vacuum
drying. Over the couse of five trials, the yield only slightly decreased, which demonstrated that
complex 1 had good recyclability (Fig. 4).
Fig. 4 Recycling test for complex 1
10

3.6 Proposed mechanism
According to previous reported [17],
a plausible mechanism for synthesis of
bis(indolyl)methane catalyzed by complex 1 was proposed in Scheme 3. Firstly, the carbonyl
group of benzaldehyde is activated by titanium salophen complex 1. Then C3 atom of indole
attacks to the activated carbonyl group to form an intermediate, which subsequently dehydrates to
form the other intermediate with a double bond. Finally, a second molecule of indole attacks
double bond of this intermediate to produce bis(indolyl)methane.
Scheme 3 Proposed mechanism for the synthesis of bis(indolyl) methane
4. Conclusion
In summary, we have successfully synthesized an µ-oxo-bridged binuclear Lewis acid of
titanium(IV) salophen perfluorooctanesulfonate. This complex showed good air-stability, high
thermostability and highly catalytic efficiency in Friedel-crafts reaction of aldehyde/ketone with
indoles. Furthermore, it can be reused five times. Compared to reported methods, this protocol
showed considerable advantages such as low catalyst loadings, mild reaction conditions, short
reaction time, general applicability, high efficiency and good reusability.
Acknowledgment
The authors thank the National Natural Science Foundation of China (21802093), the Shanxi
Province Science Foundation for Youths (201701D221035), Scientific and Technological
Innovation Programs of Higher Education Institutions in Shanxi (2019L0408), the PhD Start-up
11

Foundation of Shanxi Medical University (03201501) and the Key Research and Development
Projects of Shanxi Province (201803D31070) for the financial support.
Appendix A. Supplementary material
Supplementary data associated with this article can be found in the online version, at
1
https://doi.org/10.1016/j.inoche.2018.XXX. These data include copies of IR, H NMR, 19F NMR,
1
and HRMS spectra of catalyst and H NMR, 13C NMR spectra of all bis(indolyl)methanes
derivatives.
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14

Highlights
►
A general and mild protocol for the synthesis of bis(indolyl) methane derivatives
► Complex [{Ti(salophen)H2O}2O][OSO2C8F17]2 exhibited high catalytic activity.
►
►
►
Only 1 mol% catalytic amount of catalyst was used.
The catalyst can be reused five times.
A plausible mechanistic approach has also been proposed.

Declaration of interests
☐ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
We declare that we have no conflict of interest, and have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this paper.
Ningbo Li
Basic Medical college
Shanxi Medical University
ningboli@sxmu.edu.cn