Salicylato titanocene complexes as cooperative organometallic lewis acid and bronsted acid catalysts for three-component mannich reactions

Article abstract of DOI:10.1002/chem.201402438

A binary acid system has been developed that features an air-stable organometallic precursor, titanocene dichloride, and simple organic cooperative Bronsted acids, which allowed for mild and highly efficient Mannich reactions of both aryl and alkyl ketones with excellent yields and satisfactory diastereoselectivity. Mechanistic studies, including ¹H NMR titration, X-ray structure analyses as well as isolation of catalytically active species, elucidated the dramatic synergistic effects of this new binary acid system.

Full text of DOI:10.1002/chem.201402438

DOI: 10.1002/chem.201402438
Communication
&
Metallocenes
Salicylato Titanocene Complexes as Cooperative Organometallic
Lewis Acid and Brønsted Acid Catalysts for Three-Component
Mannich Reactions
Ya Wu, Chun Chen, Gai Jia, Xuyang Zhu, Huaming Sun, Guofang Zhang, Weiqiang Zhang,*
and Ziwei Gao*[a]
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reoselectivities. To the best of our knowledge, this is the first
time that an organometallic binary catalyst with cooperative
dual activation is used in CÀC bond-forming reactions. Mecha-
nistic studies, including 1H NMR spectroscopy titration, X-ray
structure analyses as well as isolation of catalytic active species
have been used to elucidate the mechanism of this new binary
acid catalysis system.
Abstract: A binary acid system has been developed that
features an air-stable organometallic precursor, titanocene
dichloride, and simple organic cooperative Brønsted acids,
which allowed for mild and highly efficient Mannich reac-
tions of both aryl and alkyl ketones with excellent yields
and satisfactory diastereoselectivity. Mechanistic studies,
1
including H NMR titration, X-ray structure analyses as well
We were interested in the catalytic activity of [Cp2TiCl2] and
its derivatives because titanocene dichloride is abundant and
has a stable sandwich structure that is suitable for devising or-
ganometallic Lewis acids.[12] The Mannich reactions have been
developed as model reactions to evaluate the catalytic activity
of conventional Lewis acids or Brønsted acids.[13] The prelim-
inary experiment using [Cp2TiCl2] alone was unsuccessful in the
direct three-component Mannich reaction of acetophenone,
benzaldehyde and aniline. A survey of Lewis acids of metallo-
cenes unveiled that oxygen donor ligands could be used to
fine tune the acidity of a metallic centre by entering its inner
coordination sphere.[14] With the assistance of benzoic acid, Ti
catalyst was slightly activated, and the Mannich reaction using
benzoic acid and [Cp2TiCl2] afforded b-amino ketone with 19%
yield (Scheme 1). In light of a synergistic effect in CÀC forming
as isolation of catalytically active species, elucidated the
dramatic synergistic effects of this new binary acid
system.
Cooperative catalysis has become a powerful strategy to
access unique reactivity and selectivity in synthetic organic
chemistry.[1] In particular, the binary acid system has been de-
veloped as a successful model to achieve catalytic coopera-
tion.[2] Varying the Brønsted acid, Lewis acid or both can tune
the acidity of binary catalysts, and therefore activate organic
substrates for a desirable catalytic cycle.[3] Binary acid catalysts
consist of Lewis acids of metal salts such as MgII,[4] ScIII,[5] InIII,[6]
CuII[7] or TiIV[8] and Brønsted acids such as HOTf, TsOH and
PhCOOH are particularly active in promoting mild CÀC bond-
forming reactions. Recently, sophisticated Brønsted acids were
designed to participate in binary acid catalysis.[9] Up to now,
most of the Lewis acids in binary acid catalyst systems were in-
organic salts or complexes, for which it is difficult to tune the
acidity and therefore tailor for cooperative catalysis. In this
context, the introduction of organometallic complexes as
Lewis acids for binary acid catalyst system is highly desirable,
due to their kinetic stability, diverse molecular structures and
electronically tuneable metallic acid centres.[10] Moreover, the
coordination of soft organometallic acceptors with hard
donors of Brønsted acids might provide a new dimension for
cooperative binary acid catalysis and provide new reactivity
and selectivity patterns. However, the preparation of organo-
metallic Lewis acids generally requires tedious multi-step syn-
theses which require not only judicious selection of sophisti-
cated co-ligands to stabilize Lewis acid counterparts but also
air-sensitive intermediates.[11] Thus, examples of organometal-
lics as Lewis acids in cooperative binary acid catalysis are rare.
Herein, we discuss a binary acid system featuring an air-stable
organometallic precursor, titanocene dichloride, combined
with simple organic cooperative Brønsted acids, which allowed
for mild and highly efficient Mannich reactions of both aryl
and alkyl ketones with excellent yields and satisfactory diaste-
Scheme 1. [Cp2TiCl2] accelerated Mannich reactions in the presence of
Brønsted acids.
reactions using binary catalysts of multi-functional Brønsted
acids,[9] we tested the reactivity of binary acid systems of
[Cp2TiCl2] with a series of ortho-functionalized benzoic acids.
The Mannich reaction using anthranilic acid and phthalic acid
afforded 15 and 29% isolated yield, respectively, indicating
that the amino group at ortho-position to aromatic carboxylic
acid was not helpful for the reaction. Interestingly, salicylic acid
drastically accelerated the titanocene-catalysed Mannich reac-
tion. After stirring for one hour, the condensation afforded
ketone product with 97% yield. Three control reactions using
phenol and two bidentate derivatives indicated that b-hydroxyl
and carboxyl groups were preferential functional groups for
the reaction. The key role of the phenol group in salicylic acid
was further demonstrated by using aspirin as an additive, in
which the yield of the condensation product dropped sharply
to 63%.
[a] Dr. Y. Wu, C. Chen, G. Jia, X. Zhu, Dr. H. Sun,+ Prof. G. Zhang,+
Prof. W. Zhang, Prof. Z. Gao
Key Laboratory of Applied Surface and Colloid Chemistry, MOE
School of Chemistry and Chemical Engineering
Shaanxi Normal University, Xi’an 710062 (P.R. China)
Fax: (+86)29-81530727
E-mail: zwq@snnu.edu.cn
zwgao@snnu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402438.
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Table 1. The effect of substituted salicylic acids and their analogues on
[Cp2TiCl2]-catalysed Mannich reaction.[a]
Table 2. Titanocene binary-acid-catalysed direct three-component Man-
nich reactions.[a]
Entry
Brønsted acid
Yield [%][b]
1
2
3
4
5
6
7
8
4-methoxysalicylic acid
salicylic acid
2-hydroxy-1-naphthoic acid
5-chlorosalicylic acid
5-nitrosalicylic acid
3-hydroxy-2-naphthoic acid
2,3-dihydroxybenzoic acid
2,4-dihydroxybenzoic acid
thiosalicylic acid
97
97
93
86
69
61
32
27
25
19
12
Entry
R1
R2
R3
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
1
1
5
1
5
1
1
12
1
12
12
5
5
5
5
5
1
5
4a, 97
4b, 90
4c, 82
4d, 86
4e, 82
4 f, 91
4g, 90
4h, 81
4i, 83
4j, 77
4k, 78
4l, 86
4m, 79
4n, 70
4o, 75
4p, 79
4q, 88
4r, 97
p-CH3
p-Cl
H
9
10
11
5-sulfosalicylic acid
no Brønsted acid
p-OCH3
p-Cl
p-Cl
p-OCH3
p-Cl
H
H
H
H
H
H
[a] Unless otherwise noted, all reactions were carried out with 1.0 mmol
of aldehyde, 1.1 mmol of amine, and 2.0 mmol of ketone in the presence
of [Cp2TiCl2] (0.05 mmol) and salicylic acid (0.10 mmol) at 258C for 1 h.
[b] Isolated yields were obtained after purification by column chromatog-
raphy.
p-CH3
p-CH3
p-NO2
H
9
p-OCH3
p-NO2
p-OCH3
H
H
H
H
H
10
11
12
13
14
15
16
17
18
H
p-NO2
m-CH3
o-OCH3
o-Cl
H
H
H
H
H
Further experiments demonstrated the delicate accelerating
effect of salicylic acids on the titanocene-catalysed Mannich re-
actions. These results indicated that the coordination between
the Brønsted acids and organometallic centre was crucial for
the catalytic activities of binary catalysts (Table 1). Adding an
electron-donating methoxy group on the aromatic ring of sali-
cylic acid showed no significant effect on the catalytic activity
of the Mannich reaction (Table 1, entry 1). In comparison, sali-
cylic acids bearing electron withdrawing substituents such as
ÀCl and ÀNO2 (entries 4 and 5) decreased the yields of the
condensation. Interestingly, 2-hydroxy-1-naphthoic acid
(entry 3) featuring an aromatic b-hydroxybenzoic acid structure
was shown to be a valid ligand, although the reaction using 3-
hydroxy-2-naphthoic acid (entry 6) afforded 61% yield. It was
also found that extra donor atoms suppressed the cooperative
accelerating of acid ligands. For instances, 3-hydroxysalicylic
acid (2,3-dihydroxybenzoic acid) led to only 32% yield of the
Mannich reaction (entry 7). Neither 2,4-dihydroxybenzoic acid
nor 5-sulfosalicylic acid produced the condensation product
with more than 30% yield (entries 8 and 10). Titanocene di-
chloride and thiosalicylic acid, which readily form a stable com-
plex, were not an effective catalyst (entry 9), indicating the
stable chelation might be an unfavourable coordination mode.
These findings led us to the discovery of a new protocol for
the organometallic binary-acid-catalysed direct three-compo-
nent Mannich reaction. The reaction employed 5 mol% of
[Cp2TiCl2], 10 mol% of salicylic acid, 1.0 equiv of aldehyde,
1.1 equiv of aniline and 2.0 equiv of acetophenone at 258C.
Aniline was not just a substrate, but also an HCl scavenger
that accelerated the formation of binary catalyst from
[Cp2TiCl2] and salicylic acid. The scope and limitation of the
new catalyst system were evaluated with a range of aromatic
aldehydes, amines and ketones involving electron-donating or
electron-withdrawing substituents (Table 2). The reaction out-
come was not significantly affected by substituents with differ-
ent electron properties, such as aldehydes containing chloro
(4e, 4 f) or methoxy (4d, 4g) groups, anilines with chloro (4c)
o-OCH3
o-Cl
m-OCH3
H
H
m-OCH3
[a] Unless otherwise noted, all reactions were carried out with 1.0 mmol
of aldehyde, 1.1 mmol of amine, and 2.0 mmol of ketone in the presence
of [Cp2TiCl2] (0.05 mmol) and salicylic acid (0.10 mmol) at 258C. [b] Isolat-
ed yields were obtained after purification by column chromatography.
or methyl (4b) groups and ketones with methoxy groups (4i,
4k). Aldehydes with chloro (4 f) or methoxy (4g) substituents
led to excellent results (90–91% yield) when 4-methyl aniline
was used. Anilines and ketones with nitro substituents (4h, 4j,
4k) afforded good yield (77–81%), albeit with longer reaction
time (12 h). As expected, meta-substituted aldehyde and ani-
line (4l, 4q) did not result in a lower activity. Notably, the steri-
cally hindered ortho-substituted aldehydes or anilines (4m–4p)
still furnished the desired product in more than 70% yield.
The binary acid catalyst composed of [Cp2TiCl2] and salicylic
acid was successfully applied in the Mannich reactions of ali-
phatic ketones under optimized conditions (Scheme 2 and
Table S1 in the Supporting Information). The catalytic Mannich
condensation of 3-pentanone, benzaldehydes and anilines af-
Scheme 2. Mannich reactions of aliphatic ketones catalysed by titanocene
binary acid system.
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forded the products (6a–g) in 77–87% yields and 61/39 to 78/
22 anti:syn diastereomeric ratio (d.r.) that was determined by
1H NMR spectroscopy,[15] whereas cyclohexanone converted to
the condensation product (6j) in 89% yield with a higher 91:9
anti:syn d.r. Open chain ketones, acetone and 2-hydroxyace-
tone, afforded the desired Mannich bases in 56 and 89% yield
(6h and 6i), respectively.
clined gradually with the addition of aniline. After 1.0 equiv of
aniline was added into the mixture, monosalicylato titanocene
chloride II was consumed gradually. Finally, all of I reacted with
salicylic acid in the presence of 2.0 equiv of aniline. The mix-
ture stood for 110 min to form bis-acid substituted titanocene
IV and a small amount of II and III. These observations clearly
demonstrated the ligand substitution process of the binary
acid catalyst system. It can be concluded that in the Mannich
reaction, pre-catalyst titanocene dichloride readily converted
into three detectable titanocene species containing one or two
salicylates, and presumably one of them was the organometal-
lic binary acid catalyst.
1H NMR spectroscopy experiments were performed to unveil
the mechanistic details of the catalytic species of the com-
bined acid system. To mimic the binary catalyst system,
[Cp2TiCl2] and 2.0 equiv of salicylic acids were mixed in CDCl3.
The characteristic cyclopentadienyl (Cp) protons could be used
as a probe to measure the formation of new titanocene com-
plexes. Four characteristic Cp resonance peaks were observed
To explore the possible catalytic species, we further pre-
pared the titanocene complexes. Our previous research on the
coordination chemistry of titanocene dichloride and salicylic
acids allowed for the isolation and full characterization of sali-
cylato titanocenes III.[16] Although the coordination of
[Cp2TiCl2] and salicylic acid in solution in the presence of ani-
line has been detected, the large-scale preparation of pure ti-
tanocene IV is still a synthetic challenge due to the lability and
complicated coordination modes of salicylic acid to the soft Ti
centre. Herein, we developed a new approach to prepare Ti
complex IV (Scheme 4), in which 5-sulfosalicylic acid facilitated
the ligand substitution of chloride with salicylic acid (see the
Supporting Information). By reacting with HNTf2, III converted
to mono-substituted salicylato V, an analogue of the unstable
chloride complex II. By comparing the chemical shifts of Cp
protons of three isolated Ti species, the order of their Lewis
acidities was determined to be IV>V>III. In addition, we also
found that IV spontaneously degraded to III by releasing one
salicylato ligand in CDCl3 and complex III was transformed into
1
by H NMR spectroscopy (Figure 1), which were Cp protons of
Figure 1. 1H NMR spectra of a titration of a mixture of [Cp2TiCl2] (1.0 equiv)
1
IV with the insertion of salicylic acid by H NMR spectroscopy
1
!
^
and salicylic acid (2.0 equiv) with PhNH2. I [Cp2TiCl2]; II [Cp2TiCl(h -
analysis (see the Supporting Information, Scheme S2).
Control experiments were carried out under the same condi-
tions as the original protocol (Tables 1, 2 and Table S1 in the
Supporting Information) in order to evaluate the activities of
isolated titanocene species and hopefully identify the true cat-
alyst (Table 3). Not surprisingly, [Cp2TiCl2] (I) was almost inert in
catalysing the Mannich reaction; only 12% yield of amino
ketone product was isolated (Table 3, entry 2). The chelated h2-
salicylato titanocene III could accelerate the reaction with
moderate 59% yield (Table 3, entry 3), whilst bis-salicylato tita-
nocene IV catalysed the conden-
2
1
&
*
HSal)]; III [Cp2Ti(h -Sal)]; IV [Cp2Ti(h -HSal)2]
titanocene dichloride I at d 6.59 ppm, a putative salicylato ti-
tanocene monochloride II at d 6.61 ppm, salicylato chelate III
at d 6.43 ppm, and bis-salicylato titanocene IV at d 6.68 ppm
(Scheme 3). No coordination occurred, and only one Cp singlet
of I was detected without adding base. When adding aniline,
three new titanocene complex species formed. We found that
the Cp resonance of II increased while the resonance of I de-
sation nearly quantitatively, af-
fording an isolated yield of 98%
(Table 3, entry 3). These results
suggested that IV might be the
active catalyst. This hypothesis
was further supported by the
Mannich reactions catalysed by
III with 1 equiv of salicylic acid,
which afforded 95% yield
(Table 3, entry 5). The accelera-
tion effect of salicylic acid could
result from the conversion of III
to IV in situ. The monosalicylate
Ti complex II is kinetically unsta-
Scheme 3. Various salicylato titanocene complexes derived from [Cp2TiCl2] and salicylic acid in the presence of ani-
line.
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Table 3. The activities of titanocenes species of the binary acid catalysis
system.[a]
Entry
Titanocenes
Yield [%][b]
1[c]
2
3
4
5[e]
6
[Cp2TiCl2]/H2-Sal[d]
[Cp2TiCl2] (I)
[Cp2Ti(h2-Sal)] (III)
[Cp2Ti(h1-HSal)2] (IV)
[Cp2Ti(h2-Sal)] (III)/H2-Sal
[Cp2Ti(h1-HSal)N(Tf)2] (V)
97
12
59
98
95
38
[a] Reaction conducted with 1.0 mmol of benzaldehyde, 1.1 mmol of ani-
line, and 2.0 mmol of acetophenone in the presence of 0.05 mmol of cat-
alyst at 258C for 1 h. [b] Isolated yields were obtained after purification
by column chromatography. [c] [Cp2TiCl2] (0.05 mmol) and H2-Sal
(0.10 mmol) [d] H2-Sal represents salicylic acid. [e] [Cp2Ti(h2-Sal)]
(0.05 mmol) and H2-Sal (0.05 mmol).
excellent yields as well as satisfactory diastereoselectivities.
Mechanistic studies strongly supported a dual activation path-
way. Owing to the synergistic effect, the condensation pro-
ceeded smoothly under relatively mild conditions. [Cp2Ti(h1-
HSal)2] (IV) is proposed to be the catalytically active species
based on 1H NMR spectroscopy analysis and control experi-
ments. These findings provided new insights into the chemis-
try of cooperative catalysis with organometallic Lewis acids.
Scheme 4. The synthesis and conversion of various titanocene complexes.
ble and the isolation of pure complex is technically impossible.
Thus, its stable analogue V was tested and afforded 38% yield
(Table 3, entry 6), which ruled out the possibility of II as cata-
lyst.
A
proposed cooperative catalytic cycle is outlined in
Scheme 5. Titanocene dichloride I pre-catalyst is activated by
salicylic acid (H2-Sal) and transformed to binary acid catalyst IV.
The ketone inserts into the labile TiÀO bond of IV. In transition
state A, the incoming ketone is deprotonated, in which the
enolation is accelerated cooperatively as the carbonyl coordi-
nate to oxophilic Ti and the leaving salicylato ligand shuttles
the proton. The imine is activated by protonation with a Brønst-
ed acid.[17] The key step of carbon-carbon bond formation is il-
lustrated in transition state B. The coordinated enolate then
undergoes addition to the aldimine, which is activated by hy-
drogen bonding from the hy-
Experimental Section
General procedure
A nitrogen-flushed 10 mL test tube, equipped with a magnetic stir-
rer and a septum, was charged with benzaldehyde (1.0 mmol), ani-
line (1.1 mmol), and the aromatic ketone (2.0 mmol) in one portion.
[Cp2TiCl2] (0.05 mmol) and salicylic acid (0.10 mmol) was added at
08C and stirred for 15 min. The reaction mixture was heated to
258C and stirred until the reaction was completed as indicated by
TLC, then the reaction mixture was quenched with distilled water
droxyl group. This transition
state showcases the cooperative
nature of this binary acid
system. Once the product is re-
leased, Ti chelate (III) is formed
and the titanium (IV) catalyst is
regenerated from III by the coor-
dination of salicylic acid (Table 3,
entry 5).
In conclusion, a new coopera-
tive catalysis system featuring
the synergistic effects of organo-
metallic Lewis acids and Brønst-
ed acids was developed for Man-
nich reactions. The binary cata-
lyst system successfully catalysed
the direct three-component
Mannich reaction of both aro-
matic and aliphatic ketones to
form various b-amino ketones in Scheme 5. Proposed mechanism of titanocene binary acid catalysis system in Mannich reactions.
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(5.0 mL). The aqueous phase was extracted with dichloride meth-
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to give the desired product. The crude product was purified by
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Acknowledgements
We acknowledge the 111 Project (B14041), Innovative Research
Team in University of China (IRT1070), the grant from National
Natural Science Foundation of China (21271124, 21272186),
the grant from Fundamental Doctoral Fund of Ministry of Edu-
cation of China (20120202120005), the Fundamental Research
Funds for the Central Universities (GK201302015) and Natural
Science Basic Research Plan in Shaanxi Province of China
(2012JM2006) for financial support. We also thank Prof. J. Xiao,
Prof. C. Wang, and Prof. D. Xue for useful discussions.
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Keywords: Brønsted acids
catalysis · organometallic Lewis acid · salicylic acid
·
CÀC coupling
· cooperative
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Received: March 2, 2014
Published online on && &&, 0000
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Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
&
Metallocenes
Y. Wu, C. Chen, G. Jia, X. Zhu, H. Sun,
G. Zhang, W. Zhang,* Z. Gao*
&& – &&
Salicylato Titanocene Complexes as
Cooperative Organometallic Lewis
Acid and Brønsted Acid Catalysts for
Three-Component Mannich Reactions
A binary acid system has been devel-
oped that features an air-stable organo-
metallic precursor, titanocene dichloride,
and simple organic cooperative Brønst-
ed acids, which allowed for mild and
highly efficient Mannich reactions of
both aryl and alkyl ketones with excel-
lent yields and satisfactory diastereo-
selectivity (see scheme). Mechanistic
studies were performed to shed light
on the dramatic synergistic effects of
this new binary acid catalysis system.
Synthetic Methods
The coordination of soft organometallic acceptors with hard
donors of Brønsted acids generates a new dimension for
cooperative catalysis, providing unique reactivity and
selectivity patterns. In their Communication, on page &&,
Y. Wu et al. disclose a novel and simple binary acid system
featuring an air stable organometallic precursor, Cp2TiCl2
and salicylic acids, which allowed for mild and highly
efficient Mannich reactions. The mechanistic
experimentation reveals the cooperative catalysis in play
between the Lewis acid centre of titanocene and the
cooperative Brønsted acid. The study nicely demonstrates
the power of binary catalysis in organic synthesis.
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ