Strong Lewis acid air-stable cationic titanocene perfluoroalkyl(aryl) sulfonate complexes as highly efficient and recyclable catalysts for C-C bond forming reactions

Article abstract of DOI:10.1039/c4dt00549j

A series of strong Lewis acid air-stable titanocene perfluoroalkyl(aryl) sulfonate complexes Cp₂Ti(OH₂)₂(OSO ₂X)₂·THF (X = C₈F₁₇, 1·THF; X = C₄F₉, 2·H₂O· THF; X = C₆F₅, 3) were successfully synthesized by the treatment of Cp₂TiCl₂ with C₈F ₁₇SO₃Ag, C₄F₉SO₃Ag and C₆F₅SO₃Ag, respectively. In contrast to well-known titanocene bis(triflate), these complexes showed no change in open air over three months. TG-DSC analysis showed that 1·THF, 2·H ₂O·THF and 3 were thermally stable at 230 °C, 220°C and 280°C, respectively. Conductivity measurements showed that these complexes underwent ionic dissociation in CH₃CN solution. X-ray analysis results confirmed that 2·H₂O·THF and 3 were cationic. ESR spectra showed that the Lewis acidity of 1·THF (1.06 eV) was higher than that of Sc³⁺ (1.00 eV) and Y³⁺ (0.85 eV). UV/Vis spectra showed a significant red shift due to the strong complex formation between 10-methylacridone and 2·H₂O·THF. Fluorescence spectra showed that the Lewis acidity of 2 (λ_em = 477 nm) was higher than that of Sc³⁺ (λ_em = 474 nm). These complexes showed high catalytic ability in various carbon-carbon bond forming reactions. Moreover, they show good reusability. Compared with 1·THF, 2·H₂O·THF and 3 exhibit higher solubility and better catalytic activity, and will find broad applications in organic synthesis. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4dt00549j

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Strong Lewis acid air-stable cationic titanocene
perfluoroalkyl(aryl)sulfonate complexes as highly
efficient and recyclable catalysts for C–C bond
forming reactions†
Cite this: Dalton Trans., 2014, 43,
11696
Ningbo Li,a Jinying Wang,a Xiaohong Zhang,a Renhua Qiu,*a,c Xie Wang,a
Jinyang Chen,a Shuang-Feng Yin*a and Xinhua Xu*a,b
A series of strong Lewis acid air-stable titanocene perfluoroalkyl(aryl)sulfonate complexes Cp2Ti(OH2)2-
(OSO2X)2·THF (X = C8F17, 1·THF; X = C4F9, 2·H2O·THF; X = C6F5, 3) were successfully synthesized by the
treatment of Cp2TiCl2 with C8F17SO3Ag, C4F9SO3Ag and C6F5SO3Ag, respectively. In contrast to well-
known titanocene bis(triflate), these complexes showed no change in open air over three months.
TG-DSC analysis showed that 1·THF, 2·H2O·THF and 3 were thermally stable at 230 °C, 220 °C and
280 °C, respectively. Conductivity measurements showed that these complexes underwent ionic dissociation
in CH3CN solution. X-ray analysis results confirmed that 2·H2O·THF and 3 were cationic. ESR spectra showed
that the Lewis acidity of 1·THF (1.06 eV) was higher than that of Sc3+ (1.00 eV) and Y3+ (0.85 eV). UV/Vis
spectra showed a significant red shift due to the strong complex formation between 10-methylacridone and
2·H2O·THF. Fluorescence spectra showed that the Lewis acidity of 2 (λem = 477 nm) was higher than that of
Sc3+ (λem = 474 nm). These complexes showed high catalytic ability in various carbon–carbon bond forming
reactions. Moreover, they show good reusability. Compared with 1·THF, 2·H2O·THF and 3 exhibit higher
solubility and better catalytic activity, and will find broad applications in organic synthesis.
Received 21st February 2014,
Accepted 27th May 2014
DOI: 10.1039/c4dt00549j
www.rsc.org/dalton
bifunctional titanocene-catalyzed (Cp2TiCl2/Zn/Ac2O/R3P; R =
t-Bu, 4-OMeC6H4) multicomponent coupling based on the
Introduction
Since the discovery of the Zeigler–Natta catalyst, titanium(IV)
compounds, derived from halide, alkoxide, phenolate, or
triflate ligands, have attracted much interest in the past few
decades due to their extensive application in organic syn-
thesis.1 Among them, the titanocene complexes have attracted
much attention because of their high potential in catalysis.2
Recently, many research groups have made great contributions
to the development of highly efficient catalytic systems based
on titanocene complexes.3 For example, Ashfeld developed a
redox- and Lewis acid-relay catalysis, resulting in a convergent
assembly of 1,4-diynes, 1,5-enynes, unsymmetrical diaryl-
ethynyl methanes, and β-alkynyl ketones.4 Kambe et al. found
that the Cp2TiCl2/n-BuMgCl catalytic system shows high efficiency
and regioselectivity in C–Si5 and C–C bond-forming reactions.6
Huang et al. reported titanocene-catalyzed dehydroxylative
radical coupling of hemiaminal with active alkenes.7 Roy et al.
demonstrated a titanocene(III) chloride (Cp2TiCl) mediated
radical induced Wagner–Meerwein-type rearrangement, for the
preparation of homoallyl amines and substituted alkenes
stereoselectively.8 Among these catalytic systems, most of
them4–8 focus on the TiIV–TiIII multivalent ability. However,
their potential as air-stable Lewis acid catalysts for organic syn-
thesis has rarely been studied, which may be owing to the
lower Lewis acidity of Cp2TiCl2 and its derivatives.9
To increase the Lewis acidity of the titanocene complexes,
one method is to attach electron-withdrawing group(s) on
titanium. For example, titanocene bis(triflate) Cp2Ti(OSO2CF3)2
was successfully synthesized by Thewalt and Klein,10 and was
employed by the groups of Bosnich and Collins for the for-
mation of C–C bonds.11 However, the anhydrous titanocene
bis(triflate) was hygroscopic11a and easily formed the aquo
aState Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha, 410082, China.
E-mail: xhx1581@hnu.edu.cn, renhuaqiu@hnu.edu.cn, sf_yin@hnu.edu.cn;
Tel: +86-731-88821546
bState Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjing,
300071, PR China
cDepartment of Applied Chemistry, Graduate School of Engineering,
Osaka University, Suita, 565-0871 Osaka, Japan
†Electronic supplementary information (ESI) available: CIF files of 2·H2O·THF
and 3, 1H and 13C NMR spectra, MS spectral characterization data for com-
pounds in application reaction; the copies of all compounds’ spectra including
the 1H NMR, 13C NMR spectra and the 1H NMR and 19F NMR spectra of com-
plexes 1·THF, 2·H2O·THF and 3. CCDC 894849 and 938518. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4dt00549j
11696 | Dalton Trans., 2014, 43, 11696–11708
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complexes Cp2Ti(OH2)2(OSO2CF3)2·THF (4·THF),11d which hexane into a saturated solution of complexes in THF. An
were also active as Brønsted and/or Lewis acid catalysts;11a–c ORTEP representation of 2·H2O·THF and 3 and selected bond
Brønsted acidity was disadvantageous for applications invol- lengths and angles are shown in Fig. 1 and 2. It is clear that
ving asymmetric catalysis.11f Recently, Otera and co-workers the titanocene component in 2·H2O·THF and 3 is cationic,
found that the longer perfluorooctanesulfonate groups could while the Cp2Ti(OSO2CF3)2 possesses a covalent structure.10
be used as effective counter anions to provide air-stable and The anhydrous titanocene bis(triflate) [Cp2Ti(OSO2CF3)2]
water-tolerant organometallic species in sharp contrast to the readily formed aquo complexes [Cp2Ti(OH2)2(OSO2CF3)2],
corresponding hygroscopic organometallic triflates.12 Based which are cationic complexes.11d The titanium atom in the cat-
on this idea and as part of our ongoing efforts devoted to ionic ion is coordinated by two water molecules, which lie on
metallocene complexes, herein we put forth a full account the plane that bisects the angle between the Cp ring planes.
−
of synthesis and characterization of a series of air-stable The C4F9SO3−/C6F5SO3 ions, the dissociated H2O molecules,
titanocene perfluoroalkyl(aryl)sulfonate complexes Cp2Ti(OH2)2- and the solvating ligand THF are packed around the complex
(OSO2X)·THF (X = C8F17, 1·THF; X = C4F9, 2·H2O·THF; X = cationic ion in such a way that their oxygen atoms point towards
C6F5, 3). Furthermore, their catalytic activities are assessed in the H2O ligands. The C4F9/C6F5 side chains of the anions, on
various C–C bond-forming reactions, including the Strecker
reaction, the Mannich-type reaction, allylation of aldehydes,
the Mukaiyama aldol reaction, the Friedel–Crafts acylation and
the aza-Friedel–Crafts reactions.
Results and discussion
Shown in Scheme 1 is the synthetic route to the titanocene per-
fluoroalkyl(aryl)sulfonate complexes 1–3 by treatment of
Cp2TiCl2 with silver perfluoroalkyl(aryl)sulfonate (AgX, for 1,
X = OSO2C8F17; for 2, X = OSO2C4F9; for 3, X = OSO2C6F5)
(2 equiv.) in THF or CH3CN, respectively.
1H NMR and elemental analysis results show that the
freshly prepared samples after recrystallization from THF–
hexane contained 2 or 3 water molecules along with solvating
THF for 1 and 2, and contain only two H2O molecules for 3.
Many attempts to prepare the complexes without hydrates
Fig. 1 ORTEP view of the crystal structure of 2·H2O·THF. Selected bond
lengths (Å) and angles (°): Ti1–O1, 2.026(3); Ti1–O2, 2.006(2); Ti1–C1,
2.343(4); Ti1–C2, 2.337(4); Ti1–C3, 2.336(3); Ti1–C4, 2.356(3); Ti1–C5,
failed. Since the preparation was not done in the glove box, the
2.355(3); Ti1–C6, 2.358(3); Ti1–C7, 2.363(3); Ti1–C8, 2.341(3); Ti1–C9,
solvent transformation may cause some air moisture to enter 2.353(3); Ti1–C10, 2.327(4); O2–Ti1–O1, 90.75(10). The torsion angle
between the two Cp ring planes is 46.9 degrees. The proton is omitted
for clarity.
into the reaction mixture. Upon keeping the freshly prepared
complexes 1 and 2 in open air for 2 days, the desolvation of
the THF was observed and the water molecule number
increased to 4. It should be noted that after keeping in open
air over three months, the solid samples remained as dry crys-
tals or powder and exhibited no sign of skeleton change upon
1H NMR spectroscopy analysis. Therefore, the titanocene per-
fluoroalkyl(aryl)sulfonate complexes are storable in open air,
showing a great advantage over titanocene bis(triflate) from an
operational point of view.11a
The cationic structures of 2·H2O·THF and 3 in the solid
state were confirmed by X-ray analysis. The crystals suitable for
the X-ray diffraction analysis were obtained by diffusion of
Fig. 2 ORTEP view of the crystal structure of 3. Selected bond lengths
(Å) and angles (°): Ti1–O5, 2.0226(17); Ti1–O5#, 2.0226(17); Ti1–C1,
2.351(2); Ti1–C2, 2.354(2); Ti1–C3, 2.374(2); Ti1–C4, 2.357(2); Ti1–C5,
2.364(2); Ti1–C1#, 2.351(2); Ti1–C2#, 2.354(2); Ti1–C3#, 2.374(2);
Ti1–C4#, 2.357(2); Ti1–C5#, 2.364(2); O5–Ti1–O5A, 92.75(11). The torsion
Scheme 1 Synthesis of 1·THF, 2·H2O·THF and 3.
angle between the two Cp ring planes is 47.00 degrees.
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the other hand, are clustered together to produce hydrophobic
domains. Unfortunately, in spite of many attempts, we were
unable to obtain suitable crystals of 1·THF for X-ray analysis.
However, due to the similar chemical structure, we deduced
that 1·THF could also be cationic organometallic species, which
was confirmed by conductivity measurements.
Conductivity measurements were applied to investigate
their ionic dissociation behaviour in CH3CN. The large molar
conductivity values (1·THF: Λ = 117 μS cm−1; 2·H2O·THF: Λ =
165 μS cm−1; 3: Λ = 143 μS cm−1 in CH3CN (1.0 mmol L−1) at
15 °C) are consistent with the complete ionization into a 1 : 2
electrolyte,14 implying that these complexes are cationic in the
solid state and in solution.
Table 1 The solubility of titanocene perfluoro(octane, butane, phenyl)
sulfonates in organic solvents at 25 °Ca
Solvent
1·THFb
2·H2O·THFb
3b
Acetone
MeOH
THF
EtOAc
CH3CN
Et2O
CH2Cl2
Toluene
n-Hexane
284
136
130
26
510
13
0
1541
746
827
395
1027
116
0
968
534
638
278
742
87
0
0
0
0
0
0
0
a All samples are freshly prepared and recrystallized. b Solubility g L−1
.
The thermal behaviour of three complexes 1·THF,
2·H2O·THF and 3 was investigated by TG-DSC under a N2
atmosphere (Fig. 3). The TG-DSC curves showed three stages of
weight loss. The endothermic step below 100 °C can be
assigned to the removal of water molecules corresponding to
obvious endothermic peaks. Complexes 1, 2 and 3 are thermally
stable and could remain stable up to about 230 °C, 220 °C and
280 °C, respectively. Obviously, the complex 3 shows better
thermal stability, which may be owing to the perfluorophenyl
anions. Then two weight losses of exothermic nature appear,
plausibly due to the oxidation of organic entities with a large
quantity of heat to release. We observed the removal of per-
fluoro(alkyl)phenylsulfuryl ligands at 300 °C, leaving titanium
fluoride behind. We also employed 1H and 19F NMR techniques
to analyze the 2·H2O·THF samples, which underwent thermal
treatment at 180 °C for two days, and no change was observed.
Another notable feature is the unusual solubility of 1·THF,
2·H2O·THF and 3 in acetone, THF, CH3CN, EtOAc and MeOH
(Table 1). One can see that 2·H2O·THF and 3 show higher solu-
bility in common polar organic solvents compared with the
solubility of 1·THF. It is deduced that such a difference may be
owing to the strongly lipophobic property of the perfluorooctyl
group.13 Another quite surprising behaviour is that these com-
plexes is insoluble in CH2Cl2, because CH2Cl2 is usually the
best solvent for similar titanocene bis(triflate).11d Consistently,
they are not soluble in much less polar toluene and nonpolar
n-hexane. Furthermore, as they are apparently insoluble in
water, these complexes are hydrophobic, which could be attrib-
uted to the fluoroalkyl(aryl) chain in the sulfonate ligand.
Then, we decided to estimate their Lewis acidity by different
ways, since the titanocene Lewis acid is desired to be as strongly
acidic as possible to acquire higher catalytic activity. First, to
estimate the Lewis acidity of 1 exactly, we measured the ESR
spectra of the O2•−·1 complex to determine its ΔE value,15
•−
which is the binding energy of Lewis acid metal ions with O2
.
As shown in Fig. 3 (top), the ΔE value of the titanium
complex (O2•−·1) is significantly larger (Ti4+: gzz = 2.0289, ΔE =
1.06 eV) than that of Sc(OTf)3 (gzz = 2.0304, ΔE = 1.00 eV) and
it is the largest among the ΔE values ever reported by the
Fukuzumi group.15b Since the Lewis acids with a ΔE value
larger than 0.88 eV were presumed to be capable of inducing
C–C bond-forming reactions,12a thus, it is reasonable to expect
that the Lewis acidity of 1 is higher enough to trigger syntheti-
cally useful reactions. We also applied UV/Vis spectra (Fig. 4,
middle) to qualitatively determine the Lewis acidity of 2, and
observed a significant red shift due to the strong complex for-
mation between 10-methylacridone and 2, illustrating a larger
Lewis acidity of 2. Meanwhile, we estimated the Lewis acidity
of 2 by the red shift (λem) of Lewis acid metal ions (Ti4+) with
10-methylacridone on the basis of fluorescence spectra. The
fluorescence maximum (λem) of 2 is at 477 nm (Fig. 4, bottom),
which is slightly larger than that for Sc3+ (474 nm).16 In
addition, we also employed the Hammett indicator method to
determine the acidity of 1·THF, 2·H2O·THF and 3, and found
that all of them have relatively strong acidity showing the acid
strength 0.8 < Ho ≤ 3.3 (Ho being the Hammett acidity
function).17 The characteristics of these complexes encouraged
us to evaluate their performance as Lewis acid catalysts for
carbon–carbon bond-forming reactions, such as the Strecker
reaction, the Mannich-type reaction, the Mukaiyama aldol
reaction, allylation of aldehydes, the Friedel–Crafts acylation
and the aza-Friedel–Crafts reactions.
The Strecker reaction is one of the most efficient and
straightforward methods for the synthesis of α-aminonitriles,18
which are very important intermediates for the synthesis of
α-amino acids and various nitrogen-containing heterocycles.19
In recent years, in the search for novel and efficient protocols
for the synthesis of α-aminonitriles, a broad range of metal
Fig. 3 TG-DSC curves of complexes 1·THF, 2·H2O·THF and 3.
11698 | Dalton Trans., 2014, 43, 11696–11708
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Table 2 The Strecker reaction of aldehydes/ketones with amines and
trimethylsilylcyanide catalyzed by 1·THFa
a Catalyst 1·THF (0.01 mmol); R1C(O)R2 (5; 1.0 mmol); R2NH2
(6; 1.0 mmol); TMSCN (7a; 1.2 mmol); solvent-free conditions; temp:
RT; 8a–8h, 8j–8m: 30 min; isolated yield. b Cp2TiCl2 (0.01 mmol).
c 8i: 1 h, isolated yield. d 8n–8p: 2 h, isolated yield.
aldehydes/ketones with aniline and trimethylsilyl cyanide in
the presence of 1.0 mol% of catalyst 1·THF. Aromatic alde-
hydes with electron-donating and electron-withdrawing groups
were employed. Despite variation of the reaction rate, the
yields are high. However, the yield of 9a is only 37% in the
presence of Cp2TiCl2. The aromatic aldehydes with electron-
withdrawing groups (e.g., F, Cl, and Br) exhibit higher reactivity
in the Strecker reaction than that with electron-donating
groups on the para-position of the phenyl plane (e.g., methyl
and methoxyl) (Table 2, 8a–8f, 91–96%). Gratifyingly, cinnam-
aldehyde and furfural are also tolerated in this process, and
show high reactivity with 90% and 89% yields, respectively (8g,
Fig. 4 Top: ESR spectra of O2•−·Ti4+ (1); middle: UV/Vis spectral
changes of complex formation between 10-methylacridone and 2;
bottom: fluorescence spectral changes of complex formation between
10-methylacridone and 2.
complexes, Lewis acids, solid acids and organic catalysts have 8h). In addition, the alkyl aldehydes also show good reactivity
been developed to promote this reaction.20 However, some of with 82% yield (8i) in the presence of 1·THF. Substituted phenyl-
these methods have one or more disadvantage(s) such as low amine and 8-aminoquinoline also exhibit high reactivity in
reactivity, poor selectivity, the use of organic solvents and/or this catalytic system with benzaldehyde and trimethylsiloxy-
the need for strictly anhydrous reaction conditions. It is highly nitrile and the yields are 95%, 92% and 85%, respectively (8j, 8k,
desirable to develop catalytic systems that can affect the 8l). 2-Bromobenzaldehyde was reacted with trifluoromethoxy-
Strecker reaction under solvent-free conditions with excellent aniline to obtain compound 8m in the yield of 91%. Aceto-
efficiency and stereoselectivity. We hence assessed the catalytic phenone, cyclohexanone and 4-methylcyclohexanone were reacted
efficiency with 1·THF in one-pot Strecker reaction under with aniline and trimethylsiloxynitrile, giving 8n, 8o, and 8p in
solvent-free conditions, and high efficiency and chemo- 80%, 89% and 83% yield, respectively. Thus, efficient protocols
selectivity were obtained (Table 2).
for the synthesis of α-aminonitriles have been developed.
In order to demonstrate the excellent catalytic efficiency
The Mannich-type reaction is a powerful tool for the prepa-
of 1·THF, we examined the Strecker reaction of different ration of synthetically useful β-amino carbonyl compounds,
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which are extremely important compounds as biologically the Mannich-type reaction than that with electron-donating
active molecules.21 A proper control of the three components groups (e.g., methyl and methoxyl) (Table 3, 10b–10g).
(enol silyl ether donor, amine, aldehyde acceptor) of the 2-Naphthaldehyde was also tolerated in this process, providing
Mannich-type reaction is challenging, since the side reactions compound 10h in 90% yield (Table 3, 10h). Substituted
such as the aldol reaction may lower the product yield. anilines were also examined with benzaldehyde and trimethyl-
Impressive achievements have been made in the Mannich-type (1-phenyl-vinyloxy)silane, while the electron-donating groups
reactions over various Lewis acid catalysts.22 However, the (CH3) and electron-withdrawing groups (Cl) can proceed
methods involving the aldol addition side products, longer smoothly to afford their corresponding products in high yields
reaction time, and the use of imine are “environmentally (Table 3, 10i, 10j). In addition, ketene silyl acetals also have
unfriendly” and not “atom economical”. Recently, synthetic good reactivity in the current catalytic system with benz-
methods involving the rare-earth and lanthanide triflates as aldehyde (4-chlorobenzaldehyde) and aniline in the yield of
catalysts for the Mannich-type reactions have been reported.23 87% and 89%, respectively (Table 3, 10k, 10l).
Lanthanide triflates as attractive catalysts have high catalytic
Due to the fact that the above two kinds of reactions only
activity, low toxicity, and air stability, but they are not recycl- need a weak Lewis acid catalyst, we investigated other C–C
able. Another disadvantage is that most of these catalysts bond-forming reactions requiring highly acidic Lewis acid cata-
require organic solvents as media. Thus, we assessed 3 as a lysts. The allylation of aldehydes and the Mukaiyama-aldol
catalyst (1.0 mol%) in one-pot Mannich-type reaction at room reaction mediated by a Lewis acid are the most convenient pro-
temperature under solvent-free conditions, and good-to-excel- cesses for the construction of carbon–carbon bonds in organic
lent yields were obtained (Table 3).
synthesis. This route provides a rapid access to synthesis of
As shown in Table 3, the reactions of a variety of aromatic β-hydroxy ester/ketones and homoallylic alcohol derivatives;
aldehydes with aniline and trimethyl(1-phenyl-vinyloxy)silane these motifs often exist in natural products and bioactive
(Table 3) were assessed, and the yields of 10a–10g are 88–95%. molecules.24 Several efficient Lewis acid catalysts based on tita-
However, the yield of 10a was only 28% using Cp2TiCl2 as the nium, zirconium, copper and Brønsted acids have been develo-
catalyst. The aromatic aldehydes with electron-withdrawing ped.25 But in most cases, the temperature of −20 °C to −80 °C
groups (e.g., F, Cl, Br, and NO2) exhibited higher reactivity in and strictly anhydrous conditions are required. Recently, the
highly efficient system of silica-Sc-IL/[DBIm]SbF6 developed by
Kobayashi proved to be the most promising method, which
required ionic liquids as co-catalysts.26 Therefore, a highly
efficient method for these reactions is still desired.
Table 3 The Mannich-type reaction of aldehydes, amines and enol silyl
ethers/ketene silyl acetals catalyzed by 3a
The catalytic activities of Cp2TiCl2, 1·THF, 2·H2O·THF, and
3 together with 4·THF were assessed for various carbon–
carbon bond-forming reactions. First, reactions of benz-
aldehyde with nucleophiles, such as ketene silyl acetals, enol
silyl ethers and tetraallyltin, were scrutinized (scheme in
Table 4). All reactions were carried out in the presence of
above catalysts, and the yields of the respective products are
compiled in Table 4. High yields were attained over
2·H2O·THF/3, while the other catalysts showed much lower
yields, plausibly due to their lower Lewis acidity or moisture-
sensitive features. Notably, the solvents in these reactions,
such as THF and CH3CN, were used as received owing to the
water-tolerance ability of the titanocene perfluoroalkyl(aryl)sul-
fonate complexes, in sharp contrast to titanocene of 4·THF. To
our surprise, titanocene perfluorooctanesulfonate (1·THF) only
shows moderate catalytic efficiency in the above carbon–
carbon bond-forming reactions compared with 2·H2O·THF/3.
We speculated that the relatively lower catalytic efficiency of
1·THF may be owing to the strongly lipophobic property of the
perfluorooctyl group because the perfluoro anions well wrap-
ping the cationic metal center make the lipophilic substrates
hard to approach the center metal atom for activating.
Besides, due to the strongly lipophobic property of the per-
fluorooctyl group, the complex usually exhibited moderate
solubility in common organic solvents, which may be another
reason for the decline of catalytic efficiency. Thus, 2·H2O·THF
and 3 as Lewis acid catalysts are better than 1·THF for
a Catalyst 3 (0.01 mmol); R1CHO (5; 1.0 mmol); R2NH2 (6; 1.0 mmol);
enol silyl ethers (9; 1.2 mmol); solvent-free conditions; temp: RT.,
10a–10j: 20 min, isolated yield. b Cp2TiCl2 (0.01 mmol). c 10k, 10l:
1.5 h, isolated yield.
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Table 4 Yield [%] in reactions of benzaldehyde with silyl and stannyl nucleophiles catalyzed by Cp2TiCl2, titanocene perfluoroalkyl(aryl)sulfonate
complexes and titanocene bis(triflate)s (4·THF)
Catalyst
Entry
Nu
Product
Cp2TiCl2
1·THF
2·H2O·THF
3
4·THF
1a
2b
3c
9a
9b
12
11a
11i
13a
26
19
12
79
72
80
94
90
95
89
85
90
81
76
84
a Catalyst (0.05 mol); 5a (1.0 mmol); 9a (1.2 mmol); THF (3 mL); temp: 0 °C to RT; 4 h; isolated yield. b Catalyst (0.05 mol); 5a (1.0 mmol);
9b (1.2 mmol); THF (3 mL); temp: 0 °C to RT; 10 h; isolated yield. c Catalyst (0.05 mol); 5a (1.0 mmol); 12 (0.3 mmol); CH3CN (3 mL); temp: RT;
1 h; isolated yield.
carbon–carbon bond-forming reactions. In addition, perfluoro- with different enol silyl ethers to give the desired products
octanesulfonate compounds (PFOS) have been found to be in high yields (Table 5, 15a, 15b). It is worth noting that 3
potentially toxic to animals and human beings27a and will also showed relatively high catalytic efficiency towards the
result in environmental pollution.27b However, perfluorobutane- Mukaiyama-aldol reaction and allylation of aldehydes (Table 5).
sulfonate and perfluorophenylsulfonate compounds exhibited
lower toxicity to humans and animals than PFOS,28 which acylation of aromatic compounds, which is another important
fulfills the requirement of green chemistry.
C–C bond forming reaction in organic chemistry.29 Some tra-
Later we moved to the Lewis acid-catalyzed Friedel–Crafts
Next, we mainly assessed the catalytic activities of ditional Lewis acids (such as ZnCl2, AlCl3, FeCl3, SnCl4, and
2·H2O·THF and 3. The reactions of different aldehydes and TiCl4) or strong protic acids (like HF, CF3SO3H or H2SO4) were
benzaldehyde dimethyl acetal with nucleophiles, such as utilized to catalyze the electrophilic acylation reaction.30
ketene silyl acetals, enol silyl ethers and tetraallyltin, were However, more than stoichiometric amounts of catalysts are
examined over 2·H2O·THF/3 (Table 5).
needed owing to the formation of a strong complex from the
As expected, the β-hydroxy ester/ketone derivatives and interaction between the catalyst itself and the ketone
homoallylic alcohols can be obtained in high yields in THF or product.31 Whereas the compound Sc(OTf)3 was applied in
CH3CN (Table 5). For the Mukaiyama-aldol reaction, aldehydes this reaction and a good result can be achieved,32 the high
with electron-withdrawing groups (e.g., CF3, Cl, Br, and NO2) price of Sc(OTf)3 limits its application. Furthermore, many cat-
in the phenyl plane exhibit higher reaction activity than the alysts, such as NbCl5/AgClO4 and Hf(OTf)4/AgClO4, were
aldehydes with electron-donating groups (e.g., methyl) reported as Friedel–Crafts acylation catalysts, while larger
(Table 5, 11b, 11c, 11j–11o). The cinnamaldehyde derivatives equivalents of potentially explosive perchlorate salts have to be
with a double bond are also tolerated in this catalytic system, used as co-catalysts.33
and they successfully react with ketene silyl acetals to form 1,2-
Thus, we assessed 2·H2O·THF as a catalyst for the Friedel–
addition adducts in high yields (Table 5, 11d–11h). The alkyl Crafts acylation of structurally diverse anisoles with 2.0 equiv.
aldehyde also shows good reactivity with 82% yield (Table 5, of acetic(propionic) anhydride at room temperature under
11p), while the yield of 11p with the complex 1·THF under solvent-free conditions and good yields were obtained
current conditions is only 58%. For the allylation of aldehydes, (Table 6, 18a–18i, 76–92%). Differently substituted benzene
different aromatic aldehydes also show high reactivity with (e.g. methoxy, ethoxyl, and butoxy) has high reactivity in the
tetraallyltin (Table 5, 13–13c). In addition, benzaldehyde current catalytic system with acetic anhydride and the yield is
dimethyl acetal, as a substitution of benzaldehyde, can react high from 84% to 87% (Table 6, 18a–18c). The electron-
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Table 5 The Mukaiyama-aldol reaction of aldehydes with ketene silyl
acetals/enol silyl ethers and allylation of aldehydes catalyzed by
2·H2O·THF or 3a
Table 6 Friedel–Crafts acylation of alkyl aryl ethers with anhydrides
catalyzed by 2·H2O·THFa
a Catalyst 2·H2O·THF (0.05 mmol); 16 (1.0 mmol); 17 (2.0 mmol);
solvent-free conditions; temp: rt., 4 h, isolated yield. b No catalyst or
the catalyst was Cp2TiCl2 (0.05 mmol), 12 h. c At 50 °C.
giving their corresponding products in lower yields even at
50 °C (Table 6, 18g, 18h). Meanwhile, propionic anhydride
also exhibits good reactivity with 80% yield (Table 6, 18i). Fur-
thermore, the reaction shows high regioselectivity (para-regio-
isomer > 99%). Controlled experiments were performed in the
absence of 2·H2O·THF or in the presence of Cp2TiCl2, no pro-
ducts are obtained. Therefore, in contrast to Cp2TiCl2, the
complex 2·H2O·THF can be considered to be an excellent cata-
lyst in view of catalytic efficiency and para-regioselectivity in
the Friedel–Crafts acylation.
Indoles are an important class of heterocycles that exist in
many natural products.34 Many natural and synthetic indoles
exhibit a broad range of biological activities, including anti-
cancer,35a antiangiogenic,35b antiplasmodial35c and antitumor
activities.35d Among indole derivatives, bis-indolyl alkanes,
3-alkyl indoles, and 3-diarylmethyl indoles are important class
of bioactive metabolites, which can be synthesized with Lewis
acids (e.g. InCl3 (In(OTf)3),36a Sc(OTf)3,36b FeCl3,36c CeCl3 36d or
Al(OTf)3 36e) or protic acids (e.g. HCl, HClO4, and H2SO4).
Although the synthesis of 3-alkyl indoles has been extensively
studied, the synthesis of other unsymmetrical indole deriva-
tives is still highly desirable in synthetic community since it
needs more practical procedures and mild reaction conditions.37
Herein we report the complex 3-catalyzed one-pot three-
component aza-Friedel–Crafts reactions of indoles, aldehydes,
and tertiary aromatic amines. The reactions generated the
corresponding 3-diarylmethyl indole derivatives in good yields
under mild reaction conditions (Table 7). In order to demon-
strate the good catalytic efficiency of 3, the scope of indoles
and benzaldehydes for the three-component aza-Friedel–Crafts
reactions using 3 as a catalyst was evaluated. One can see that
benzaldehydes bearing electron-withdrawing groups (F, Cl, Br,
and NO2) give the corresponding products in higher yields
a Catalyst 2·H2O·THF or 3 (0.05 mmol); R1CHO (5; 1.0 mmol) or
Ph(OMe)2 (14; 1.0 mmol); ketene silyl acetals/enol silyl ethers
(9; 1.2 mmol) or tetraallyltin (12; 0.3 mmol); THF–CH3CN (3 mL);
temp: RT; 11a–11h: 4 h; 11i–11o: 10 h; 11p: 12 h; 13a–13c: 1 h, isolated
yield. b 15a: 5 h, isolated yield. c 15b: 12 h, isolated yield.
donating groups attached to the aromatic ring enhance the than those with electron-donating groups (CH3 and OCH3)
reaction activity (Table 6, 18d–18f), but the anisole with 2-Cl (Table 7, 21b–21g). In contrast, indoles bearing electron-donat-
and 3-Br groups keeps remains intact at room temperature, ing groups (methyl) show slightly higher reactivity than those
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Table 7 The aza-Friedel–Crafts reactions of indoles, aldehydes and
N,N-dialkylaniline catalyzed by 3a
Fig. 5 (a) Catalyst 2·H2O·THF (0.05 mmol, 45 mg); (b) adding starting
materials [PhOMe (1.0 mmol, 108 mg) + Ac2O (2.0 mmol, 204 mg)];
(c) the reaction was complete as indicated by TLC; (d) adding 10 mL
n-hexane; (e) removing the liquid reaction mixture with a syringe (or
filtration) and washing the residue with hexane (three times); (f) scraping
the catalyst on the flask wall (43 mg).
with electron-withdrawing groups, like F and Cl (Table 7,
21h–21k). However, the yield of 21a was only 15% using Cp2TiCl2
as a catalyst. Meanwhile, N,N-diethylaniline can also react with
benzaldehyde and indole to give 60% yield (Table 7, 21m). It is
worth noting that no reaction was observed when 5-nitroindole
(bearing the strong electron-withdrawing group) was employed
as the substrate (Table 7, 21l).
To test the reusability of the catalyst and the reproducibility
of the catalytic performance, 1·THF or 2·H2O·THF/3 was sub-
jected to recycling experiments of above reactions (eqn (1):
5a + 6a + 7a → 8a; eqn (2): 5a + 6a + 9b → 10a; eqn (3): 5a + 9a →
11a; eqn (4): 16a + 17a → 18a). We took the Friedel–Crafts
acylation (16a + 17a → 18a) as an example for the catalyst recovery
process. As shown in Fig. 5, the catalyst can be easily recycled
by adding the solvent n-hexane (three times). Moreover, the
final recovered catalyst was analyzed by 1H NMR. It is clear
that 1H NMR spectra of the recovered catalyst are the same
as that of the catalyst 2·H2O·THF (Fig. 6), implying that the
a Catalyst 3 (0.02 mmol); R1CHO (5; 1.0 mmol); indoles (19; 1.0 mmol);
N,N-dialkylaniline (20; 1.1 mmol); solvent: CH2ClCH2Cl (3 mL); temp:
100 °C; isolated yield. b Cp2TiCl2 (0.02 mmol). c PhCHO (1.0 mmol);
5-nitroindole (1.0 mmol); N,N-dimethylaniline (20a; 1.1 mmol).
1
◇
Fig. 6 The H NMR spectral comparison of the recovered catalyst 1 in the Friedel–Crafts acylation as shown in the scheme in Table 1 ( = catalyst
△
○
peak (Cp-H); = THF peak; = recycled catalyst contains some impurities which are products and starting materials).
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Table 8 Yields of the Strecker reaction (eqn (1)); Mannich-type reaction (eqn (2)); Mukaiyama aldol reaction (eqn (3)) and Friedel–Crafts acylation
(eqn (4)) by recovered catalysta
Cycle
Yielde (%) eqn (1)a
Cat. f (%)
Yielde (%) eqn (2)b
Cat. f (%)
Yielde (%) eqn (3)c
Cat.c (%)
Yielde (%) eqn (4)d
Cat. f (%)
1
2
3
4
5
95
96
95
95
96
96
97
97
96
97
94
95
94
94
93
96
97
96
96
95
94
95
96
94
94
96
97
98
96
97
87
88
86
87
88
89
90
88
88
91
a 5a (1.0 mmol); 6a (1.0 mmol); 7a (1.2 mmol); 1·THF (0.01 mmol); rt. b 5a (1.0 mmol); 6a (1.0 mmol); 9b (1.2 mmol); 3 (0.01 mmol); RT.
c 5a (1.0 mmol); 9a (1.2 mmol); cat. 2·H2O·THF/3 (0.05 mmol); RT. d 16a (1.0 mmol); 17a (2.0 mmol); 2·H2O·THF (0.05 mmol); RT. e The isolated
yield of the desired product. f The isolated yield of the recovered catalyst.
catalyst is stable and suitable for reuse. According to this pro- wise indicated. The preparation of the catalyst was carried out
cedure, the above reactions were carried out and the results under a nitrogen atmosphere with freshly distilled solvents.
are shown in Table 8. The change in product yield was negli- THF and hexane were distilled from sodium/benzophenone.
gible in a trial of five recycling experiments.
Acetonitrile was distilled from CaH2. The NMR spectra were
recorded at 25 °C on an INOVA-400M (USA) calibrated with tetra-
methylsilane (TMS) as an internal reference. Elemental ana-
lyses were performed using a VARIO EL III. TG-DSC analysis
was performed on a HCT-1 (HENVEN, Beijing, China) instru-
Conclusion
We have synthesized and characterized a series of mono- ment. The conductivity was measured on a REX conductivity
nuclear titanocene perfluoroalkyl(aryl)sulfonate complexes. meter DDS-307. IR spectra were recorded on a NICOLET 6700
These complexes are strongly acidic and air-stable, and show FTR spectrophotometer (Thermo Electron Corporation). X-ray
high catalytic activity in the Strecker reaction, the Mannich- single crystal diffraction analysis was performed with SMART-
type reaction, allylation of aldehydes, the Mukaiyama aldol APEX and RASA-7A by Shanghai Institute Organic Chemistry,
reaction, the Friedel–Crafts acylation and the aza-Friedel– China Academy of Science. The Lewis acidity estimation
Crafts reactions. Moreover, these complexes show good reusa- was performed by means of ESR in Osaka University. UV/Vis
bility. Compared with 1·THF, 2·H2O·THF and 3 exhibit higher (SHIMADZU UV-1601) and fluorescence spectroscopy (HITACHI
solubility and better catalytic activity. Due to their high cataly- F-4600) were performed in the State Key Laboratory of
tic efficiency, stability, storability, low toxicity and reusability, Chemo/Biosensing and Chemometrics, College of Chemistry
they will find broad applications in organic synthesis.
and Chemical Engineering, Hunan University (China). 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 a pKa value of the
indicators.
Experimental section
General
Preparation of 1·THF. To a solution of Cp2TiCl2 (0.249 g,
All chemicals were purchased from Aldrich. Co. Ltd as well as 1.0 mmol) in 20 mL THF was added a solution of AgOSO2C8F17
other chemical providers and used as received unless other- (1.24 g, 2.05 mmol) in 10 mL THF. After the mixture was stirred
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at 25 °C for 1 hour in the absence of light, it was filtered. [I > 2σ(I)] R1 = 0.0294, wR2 = 0.0771; R indices (all data), R1 =
The filtrate was placed in a small jar, which was put into a larger 0.0337, wR2 = 0.0795. GOF = 1.146; CCDC no. 938518.
jar containing dry hexane (40 mL). The larger jar was sealed and
Typical procedure for the solubility of 1·THF, 2·H2O·THF
refrigerated for 24 h. The yellow crystals were obtained (744 mg, and 3. Acetone (0.5 mL) was placed in a test tube; the complex
58%). 1H NMR (400 MHz, acetone-d6): δ 7.22 (s, 10H, Cp), 3.64 to 1·THF was added gradually at room temperature. When the
3.61 (m, THF), 1.82 to 1.76 (m, THF); 19F NMR (376 MHz, amount of added 1·THF exceeded 142 mg, insoluble 1·THF
acetone-d6): δ −81.67 (t, J = 19.9 Hz, 3F, CF3–), −115.03 (s, 2F, appeared. Based on these data, the solubility of 1·THF was
–CF2–), −121.06 to 121.12 (m, 2F, –CF2–), −122.14 to −122.51 determined to be 284 g L−1. According to the same procedure,
(m, 6F, –CF2–), −123.26 to −123.33 (m, 2F, –CF2–). −126.73 to the solubilities of complexes 2·H2O·THF and 3 were determined.
−126.80 (m, 2F, –CF2–); IR(KBr): ν = 3512, 3427, 3117, 2903,
Typical procedure for conductivity measurements. Aceto-
nitrile (10 mL) was placed in a beaker; the complex 2·H2O·THF
1629, 1442, 1364, 1253, 1148, 1065, 826, 737, 641 cm−1
;
elemental analysis calculated (%) for Cp2Ti(OSO2C8F17)2 after (4.5 mg, 0.005 mmol) was added at room temperature. The
pumping for a week: C26H10F34O6S2Ti: C, 26.55; H, 0.86; probe was placed in the solution for the measurement of corre-
found: C, 26.62; H, 0.87.
lative conductivity. According to the same procedure, the con-
Preparation of 2·H2O·THF. To
(0.249 g, 1.0 mmol) in 20 mL THF was added a solution of
a solution of Cp2TiCl2 ductivities of 1·THF and 3 were measured.
ESR detection of the O2•−/1 complex. A quartz ESR tube
AgOSO2C4F9 (0.832 g, 2.05 mmol) in 10 mL THF. After the (4.5 mm i.d.) containing an oxygen-saturated solution of
mixture was stirred at 25 °C for 1 hour in the absence of light, dimeric 1-benzyl-1,4 dihydronicotinamide (BNA)2 (1.0 × 10−2
it was filtered. The filtrate was placed in a small jar, which was M) and 1·THF (1.0 × 10−3 M) in MeCN was irradiated in the
put into a larger jar containing dry hexane (40 mL). The larger cavity of the ESR spectrometer with the focused light of a 1000
jar was sealed and refrigerated for 24 h. The yellow crystals W high-pressure Hg lamp through an aqueous filter. Dimeric
1
were obtained (631 mg, 70%). H NMR (400 MHz, acetone-d6): (BNA)2, which was used as an electron donor to reduce oxygen,
δ 7.22 (s, 10H, Cp), 3.64 to 3.61 (m, THF), 1.82 to 1.76 (m, was prepared according to the literature. The ESR spectra of
THF); 19F NMR (376 MHz, acetone-d6): δ −81.81 (t, J = 20.3 Hz, the O2•−/1 complex in frozen MeCN were measured at 143 K
3F, CF3–), −115.03 (s, 2F, –CF2–), −122.04 to 122.10 (m, 2F, with JEOL X-band apparatus under nonsaturating microwave
–CF2–), −126.57 to −126.68 (m, 2F, –CF2–); IR(KBr): ν = 3439, power conditions. The g values were calibrated precisely with a
3104, 2874, 1635, 1441, 1358, 1262, 1217, 1134, 1063, 1022, Mn2+ marker, which was used as a reference.
815, 744, 703, 661 cm−1; elemental analysis calculated (%) for
Cp2Ti(OSO2C4F9)2 after pumping for a week: C18H10F18O6S2Ti: 2·H2O·THF. The formation of metal ion complexes with
C, 27.85; H, 1.30; found: C, 27.82; H, 1.35. 10-methylacridone was examined from the change in the UV/Vis
UV/Vis spectral detection of the 10-methylacridone/
Crystal data for 2·H2O·THF: C22H24F18O10S2Ti; Mr = 898.40, spectra in the presence of various concentrations of metal ions
monoclinic, space group P21/c, a = 16.1896(17) Å, b = 12.8505 (Mn+) using a Hewlett-Packard 8452 A diode array spectro-
(13) Å, c = 19.6306(15) Å; V = 3538.8(6) Å3; T = 293 (2) K; Z = 4; photometer. The formation constants were determined from
reflections collected/unique, 23 243/6888, Rint = 0.0175, final R linear plots of (A − A0)−1 versus [Mn+ −1
]
, in which A and A0 are
indices [I > 2σ(I)] R1 = 0.0536, wR2 = 0.1465; R indices (all data), the absorbance at lmax in the presence of the metal ion and
R1 = 0.0597, wR2 = 0.1484. GOF = 1.089; CCDC no. 894849. the absorbance at the same wavelength in the absence of the
Preparation of 3. To a solution of Cp2TiCl2 (0.249 g, metal ion, respectively.
1.0 mmol) in 20 mL CH3CN was added a solution of
Typical procedure for fluorescence spectral detection of
AgOSO2C6F5 (0.791 g, 2.05 mmol) in 10 mL CH3CN. After the 2·H2O·THF. The fluorescence measurement of 10-methyl-
mixture was stirred in the absence of light at room tempera- acridone/2·H2O·THF was performed on
a spectrofluoro-
ture for 2 hours, it was filtered and evaporated in a vacuum photometer. The excitation wavelength of 10-methylacridone/
and the resulting residue was diluted with 10 mL THF followed 2·H2O·THF was 413 nm in MeCN. The MeCN solutions
by five drops of dry hexane and then was kept in the refriger- were deaerated by argon purging for 7 min prior to the
ator for 24 hours, the yellow crystal was obtained (517 mg, measurements.
73%). Recrystallization of this complex in THF–hexane
produced good crystals suitable for X-ray analysis. Mp:
Crystal data refinement details
214–216 °C; 1H NMR (400 MHz, acetone-d6): δ 7.13 (s, 10H,
Cp), 19F NMR (376 MHz, acetone-d6): δ −139.33 (s, 2F, C6F5–), Refinement of F2 against all reflections. The weighted R-factor
−152.20 (s, 1F, C6F5–), −163.00 (s, 2F, C6F5–); IR(KBr): ν = 3411, wR and the goodness of fit S are based on F2, conventional
1632, 1518, 1313, 1253, 1124, 1031, 965, 823, 725 cm−1
;
R-factors R are based on F, and F is set to zero for negative F2.
elemental analysis calculated (%) for C22H14F10O8S2Ti (as two The threshold expression of F2 > 2 sigma (F2) is used only for
hydrates): C, 37.30; H, 1.99; found: C 37.28; H, 2.01. calculating R-factors (gt), etc. and is not relevant to the choice
Crystal data for 3: C22H14F10O8S2Ti; Mr = 708.35, mono- of reflections for refinement. R-Factors based on F2 are statisti-
clinic, space group C2/m, a = 14.3586 (13) Å, b = 15.8694(16) Å, cally about twice as large as those based on F, and R-factors
c = 12.0211(11) Å; V = 2593.8(4) Å3; T = 100(2) K; Z = 4; reflections based on ALL data will be even larger. Data collection: Bruker
collected/unique, 9551/2501, Rint = 0.0257, final R indices SMART; cell refinement: Bruker SAINT; data reduction: Bruker
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SHELXTL; program(s) used to solve structures: SHELXS97 MgSO4. After evaporation, the residue was subjected to silica
(Sheldrick, 1990); program(s) used to refine structures: gel column chromatography (petroleum ether–ethyl acetate =
SHELXL97 (Sheldrick, 1997); molecular graphics: Bruker 10 : 1), and colourless crystals of (11a) were obtained (196 mg,
SHELXTL; software used to prepare material for publication: isolated yield 95%). Aldehydes (5) and nucleophiles ketene
Bruker SHELXTL. CCDC-894849 and CCDC-938518 contain the silyl acetals (9a) and enol silyl ethers (9b) are commercially
supplementary crystallographic data for this paper.
available.
Typical procedure for the Strecker reaction of benzaldehyde
Typical procedure for allylation of benzaldehyde (5a) with
(5a) with aniline (6a) and trimethylsilyl cyanide (7a) catalyzed tetraallyltin (12) catalyzed by 2·H2O·THF. The complex
by 1·THF. A mixture of PhCHO (106 mg, 1 mmol), PhNH2 2·H2O·THF (45 mg, 0.05 mmol) was added to a solution of
(93 mg, 1 mmol), trimethylsilylcyanide (119 mg, 1.2 mmol) benzaldehyde (106 mg, 1.0 mmol) in CH3CN (3.0 mL). Tetra-
and catalyst 1·THF (9 mg, 0.01 mol) was stirred at room temp- allyltin (12; 0.3 mmol) was then added to the mixture at room
erature until the reaction was complete. It was subjected to temperature. After the mixture was stirred at room temperature
evaporation in a vacuum at room temperature, the residue was for an hour and monitored by TLC, it was evaporated in a
dissolved in CH2Cl2 (10 mL × 3) and the catalyst was collected vacuum at room temperature. n-Hexane (10 mL × 3) was added
by means of filtration for the next cycle of reaction. To the fil- to the residue; the catalyst was precipitated and was recovered
trate, after evaporation of the solvent a pale yellow solid by filtration for the next reaction cycle. The combined
mixture was obtained. The products 8a were isolated by silica n-hexane solution was concentrated, and then MeOH and
gel column chromatography on silica gel (petroleum ether– HCl (aq.) were added and stirred for 15 min. NaHCO3 (aq.) was
EtOAc = 8 : 1) with a yield of 95% (198 mg) as a pale yellow added for neutralization. After the mixture was subjected to
solid. Aldehydes/ketones (5) and amines (6) and nucleophiles evaporation, the as-obtained solids were dissolved in AcOEt
trimethylsilyl cyanide (7a) are commercially available.
and water. After extraction with AcOEt (three times), the
Typical procedure for the Mannich-type reaction of benz- organic layer was washed with NaCl (aq.) and dried over
aldehyde (5a) with aniline (6a) and trimethyl(1-phenyl-viny- MgSO4. After evaporation, the GLC yield was measured. Alter-
loxy)silane (9b) catalyzed by 3. The complex 3 (7 mg, 0.01 mmol), natively, the residue was subjected to silica gel column chromato-
PhCHO (106 mg 1.0 mmol), PhNH2 (93 mg, 1.0 mmol) and graphy (petroleum ether–ethyl acetate = 8 : 1) and 13a was
trimethyl(1-phenyl-vinyloxy)silane (230 mg, 1.2 mmol) obtained as a colorless oil (139 mg, isolated yield 95%). Alde-
were placed in a 50 mL round-bottomed flask. Then the hydes (5) and tetraallyltin (12) are commercially available.
mixture was stirred at room temperature until the reaction
Typical procedure for the Mukaiyama-aldol reaction of benz-
was complete as indicated by TLC. Then the solvents of the aldehyde dimethyl acetal (14) with ketene silyl acetals or enol
resulting mixture were removed by evaporation under vacuum, silyl ethers (9) catalyzed by 2·H2O·THF. The operation method
the residue was dissolved in CH2Cl2 (10 mL × 3) and the cata- is similar to Mukaiyama-aldol reaction of benzaldehyde(5a)
lyst was collected by means of filtration for the next cycle of with ketene silyl acetals (9a). The solvent was replaced with
reaction. The filtrate was subjected to volatilization and pale CH3CN. Benzaldehyde dimethyl acetal (14) and nucleophiles
yellow solids were obtained, the products 10a were isolated by ketene silyl acetals (9a) and enol silyl ethers (9b) are commer-
silica gel column chromatography on silica gel (petroleum cially available.
ether–EtOAc = 5 : 1) in yield 94% (283 mg) as a white solid.
Typical procedure for Friedel–Crafts acylation of anisole
Aldehydes (5) and amines (6) and nucleophiles ketene silyl (16a) with acetic anhydride (17a) catalyzed by 2·H2O·THF. To a
acetals (9a) and enol silyl ethers (9b) are commercially 50 mL round-bottom flask were added anisole (16a) (108 mg,
available.
1.0 mmol), acetic anhydride (17a) (204 mg, 2.0 mmol) and the
Typical procedure for the Mukaiyama-aldol reaction of benz- catalyst 2·H2O·THF (45 mg, 0.05 mmol). Then the mixture was
aldehyde (5a) with ketene silyl acetals (9a) catalyzed by stirred at room temperature until complete consumption of
2·H2O·THF. The complex 2·H2O·THF (45 mg, 0.05 mmol) and the starting material as monitored by TLC or GC-MS analysis.
ketene silyl acetal (9a) (209 mg, 1.2 mmol) were added to a After that, the residue was dissolved in n-hexane (10 mL × 3)
solution of PhCHO (5a) (106 mg, 1.0 mmol) in THF (3.0 mL) at and the catalyst was collected by means of filtration for the
0 °C. Then the temperature was raised to room temperature next cycle of reaction. The solvent was removed by evaporation
slowly. After the mixture was stirred at room temperature for in a vacuum and was then subjected to silica gel column
5 h and monitored by TLC, it was subjected to evaporation chromatography; the Friedel–Crafts acylation product (18a)
under vacuum at room temperature, the residue was dissolved was obtained: 131 mg, isolated yield 87%. Alkyl aryl ethers (16)
in n-hexane (10 mL × 3) and the catalyst was collected by and anhydrides (17) are commercially available.
means of filtration for the next cycle of reaction. To the com-
Typical procedure for the aza-Friedel–Crafts reaction of
bined hexane solution, MeOH and HCl (aq.) were added and benzaldehyde (5a) with indole (19a) and N,N-dimethylaniline
the mixture was stirred for 15 minutes. NaHCO3 (aq.) was (20a) catalyzed by the complex 3. To a 50 mL round-bottom
added for neutralization. The mixture was subjected to evapor- flask were added benzaldehyde (106 mg, 1.0 mmol), indole
ation, and the solids thus obtained were dissolved in AcOEt (117 mg, 1.0 mmol), N,N-dimethylaniline (133 mg, 1.1 mmol),
and water. After extraction with AcOEt (three times), the CH2ClCH2Cl (3 mL) and catalyst 3 (14 mg, 2 mol%). Then the
organic layer was washed with NaCl (aq.) and dried over mixture was stirred at 100 °C until complete consumption of
11706 | Dalton Trans., 2014, 43, 11696–11708
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the starting material as monitored by TLC. Then the reaction
mixture was evaporated in a vacuum, CH2Cl2 (10 mL × 3) was
added to the reaction mixture and the catalyst was filtered for
the next cycle of reaction. The combined CH2Cl2 solution was
removed by evaporation in a vacuum and was then subjected
to silica gel column chromatography; the one-pot three-com-
ponent aza-Friedel–Crafts product (21a) was obtained, white
solid, 235 mg, isolated yield 72%. Aldehydes (5) and indoles
(19) and the nucleophile N,N-dialkylaniline (20) are commer-
cially available.
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Acknowledgements
This work was supported by the NSFC (21273068, 21172061,
21373003, 21003040), the NSF of Hunan Province (11JJ5009,
14JJ7027), and the JSPS fellowship (P12035). The authors
thank Profs. J. Otera, and A. Orita (Okayama University of
Science) for the helpful discussions. S. Yin and R. Qiu thank
Profs. N. Kambe (Osaka University), L. B. Han (AIST), C. T. Au
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