Cooperative catalysis of p-aminophenol and titanocene dichloride in direct Mannich reactions with acetone

Article abstract of DOI:10.1246/cl.140705

A new binary acid system featuring an air stable organometallic precursor, titanocene dichloride and a simple Bronsted acidbase compound, was developed. The new catalyst system allowed for mild and highly efficient direct three-component Mannich reactions of both aryl ketones and alkyl ketones, in particular, acetone and its derivatives with excellent yields. Mechanistic study elucidated the dramatic synergistic effect of the new binary acid system.

Full text of DOI:10.1246/cl.140705

CL-140705
Received: July 25, 2014 | Accepted: August 25, 2014 | Web Released: December 5, 2014
Cooperative Catalysis of p-Aminophenol and Titanocene Dichloride
in Direct Mannich Reactions with Acetone
Xuyang Zhu, Chun Chen, Binxun Yu, Guofang Zhang, Weiqiang Zhang,* and Ziwei Gao*
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering,
Shaanxi Normal University, Xi’an 710062, P. R. China
(E-mail: zwgao@snnu.edu.cn, zwq@snnu.edu.cn)
A new binary acid system featuring an air stable organometallic
precursor, titanocene dichloride and a simple Brønsted acid-base
compound, was developed. The new catalyst system allowed for
mild and highly efficient direct three-component Mannich reactions
of both aryl ketones and alkyl ketones, in particular, acetone and
its derivatives with excellent yields. Mechanistic study elucidated
the dramatic synergistic effect of the new binary acid system.
The Mannich reaction is a classic organic reaction to generate
β-aminocarbonyl compounds, which are important intermediates
for the construction of various nitrogen-containing natural prod-
ucts and pharmaceuticals.1 Specifically, the direct three-component
Figure 1. Brønsted acid-base ligands cooperated with [Cp2TiCl2]-
catalyzed Mannich reactions.
Mannich reaction has made remarkable progress. In these
examples, aromatic ketones are widely used as nucleophiles,
which have been efficiently catalyzed by organocatalysts and metal
catalysts,2 whereas attempts on aliphatic ketones, such as acetone,
have not been satisfying. For acetone, organocatalysts3 required a
long reaction time to acquire almost 60% yields; metal catalysts
can slow down the reaction, but the yields have not yet been
improved.4 The low to moderate yields in the above reactions can
be attributed to the strong competition between the Mannich
reaction and Aldol reaction.5
Pleasingly, the presence of o-aminophenol led to a significant
activation of [Cp2TiCl2] to provide the desired Mannich product.
After stirring for two hours, the condensation reaction afforded a
ketone product with 79% yield. The result suggested the weak
Brønsted acidity of the phenol group could be suitable for
coordination with the Ti center, thereby adjusting the Lewis acidity
of titanocene complexes in situ for the Mannich reaction with
acetone. As a Brønsted base, an aromatic amino group could be
beneficial for generating titanium enolate. However, with the
assistance of o-phenylenediamine, which only had Brønsted base
sites, the activity of the Ti catalyst was inhibited. As control
reactions, using phthalic acid, salicylic acid, and pyrocatechol as
ligands individually, which only had Brønsted acid sites, afforded
45%-58% yields. The reaction carried out in the presence of
[Cp2TiCl2] without any ligand led to 38% yield. The results
indicated that both amino and hydroxy groups, which are sited
on the same aromatic ring as the co-Brønsted acid-base ligand
with [Cp2TiCl2], are critical to ensuring the success of the direct
Mannich reaction with acetone.
Encouraged by the preliminary results, we tested functional-
ized aminophenols as co-Brønsted acid-base ligands for
[Cp2TiCl2]-catalyzed Mannich reactions. The results of the
catalytic Mannich reaction illustrate the delicate Brønsted acid-
base effects of the new catalysis system (Table 1). The electron-
donating methyl group on the aromatic ring of o-aminophenol
(Table 1, Entry 2) decreased the yield of the reaction. In
comparison, electron-withdrawing substituents such as chloro
(Table 1, Entry 3) slightly activated the Ti catalyst. Interestingly,
from o-aminophenol to m-aminophenol to p-aminophenol, the
yields of ketones were significantly improved, indicating the
impact of steric effect on the catalysis system (Table 1, Entries 1,
4, and 5). Two control experiments using phenol or aniline as the
ligand indicated that amino and hydroxy groups on the same
aromatic ring are very important for efficient catalytic activity
(Table 1, Entries 6 and 7). It is not surprising that p-aminophenol
Cooperative catalysis using a binary acid system consisting of
a Brønsted acid and Lewis acid has emerged as a potent strategy to
access unique reactivity in synthetic organic chemistry.6 Recently,
we disclosed a binary acid system with cooperative dual activation,
featuring titanocene dichloride and salicylic acid, for three-
component Mannich reactions.7 However, for aliphatic ketones,
in particular acetone, the yield was only 56%. Our efforts revealed
that the Lewis acidity of titanocene dichloride can be adjusted by
exploiting different o-ligands. Thus, finding the suitable acidity of
the binary acid system to efficiently catalyze the Mannich reaction
with acetone and its derivatives remains a significant challenge.
Herein, as part of our continuous efforts, we report a novel
cooperative catalysis system based on titanocene dichloride as the
Lewis acid and p-aminophenol as the dual activation additive for a
mild and highly efficient direct Mannich reaction with acetone and
its derivatives. We envisioned that introducing the amino group to
the aromatic Brønsted acids could not only promote coordination
with titanocenes by adjusting electron density in the aromatic
ring, but also play an important role as a Brønsted base for
deprotonation of ketones to form titanium enolates and neutraliza-
tion of hydrogen chloride escaped from titanocene dichloride.
To test our proposal, six bifunctional aromatic compounds that
were expected to be efficient structures of cooperative Brønsted
acid-base ligands to [Cp2TiCl2] were investigated. By using
benzaldehyde, aniline, and acetone as the model substrates, we
tested the three-component Mannich reaction at 25 °C with
5 mol % [Cp2TiCl2] and 10 mol % ligands (Figure 1).
1832 | Chem. Lett. 2014, 43, 1832–1834 | doi:10.1246/cl.140705
© 2014 The Chemical Society of Japan

Table 1. Synergistic effects of [Cp2TiCl2]-catalyzed Mannich reactiona
Table 2. Mannich reactions of various aromatic aldehydes, aromatic
anilines, and ketonesa
Entry
Brønsted acid-base compound
Yieldb/%
OH
R2
R2
1
2
3
4
5
6
7
8c
o-aminophenol
4-methyl-2-aminophenol
4-chloro-2-aminophenol
m-aminophenol
p-aminophenol
phenol
79
74
80
85
88
51
40
10
[Cp2TiCl2] + H
2N
O
O
HN
HN
R3
O
CHO
+
NH2
5 mol% (1:2)
R2
R1
R4
+
+
R3
R3
25-50 °C, 2 h
R1
R1
R4
R4
b
a
Entry R1
R2
R3
R4 Yieldb/% Ratio of a:b Syn:antig
1
2
3
H
p-Cl
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
88
85
78
90
80
94
80
86
85
78
68
75
83
83
84
87
85
75
65
85
60
90
85
96
87
none
none
none
none
none
none
none
>99:1
none
none
none
none
none
none
>99:1
>99:1
>99:1
>99:1
>99:1
none
none
none
none
none
none
none
none
none
none
none
none
none
none
75:25
55:45
52:48
54:46
34:66
40:60
none
none
none
none
none
3:97
aniline
p-aminophenol
p-OCH3
aPhCHO, 1.0 mmol; PhNH2, 1.1 mmol; acetone, 27.1 mmol; catalyst,
4c m-NO2
b
c
0.05 mmol; 25 °C; 2 h. Isolated yields. Without [Cp2TiCl2].
5
6c
o-Cl
H
H
H
H
H
H
H
m-Cl
m-CH3 CH3
m-Cl
m-Cl
p-Cl
p-OCH3 C2H5 CH3
o-OCH3 C2H5 CH3
H
H
H
H
H
H
p-Cl
H
m-CH3
H
H
m-CH3 Ph
o-OCH3 Ph
7
as the only catalyst had little catalytic activity (Table 1, Entry 8).
Evidently, p-aminophenol had the best synergistic effect on the
[Cp2TiCl2]-catalyzed Mannich reaction, which afforded 88% yield
of Mannich condensation (Table 1, Entry 5).
8d
CH3 OH
C2H5 CH3
C2H5 CH3
9d
10d
11d
12d
With the optimized conditions in hand, we examined the
reactions of numerous aromatic aldehydes, aromatic amines, and
ketones to ascertain the generality and scope of the protocol
(Table 2). Aliphatic ketones, cyclic alkyl ketones, and aromatic
ketones all afforded good yields. Notably, acetone as the substrate
afforded up to 94% yield, which was difficult to achieve for many
other catalysts. It was also found that the reaction proceeded
smoothly with different kinds of aromatic aldehydes, aromatic
amines, and acetone bearing either electron-withdrawing or
-donating groups (Table 2, Entries 1-7). When ortho-, meta-,
and para-substituents of benzaldehydes and anilines were elec-
tron-withdrawing groups, the yields of the condensations were
higher than in others. An analogous trend can be observed using
acetol and 3-pentanone as the substrates (Table 2, Entries 8-14).
The Mannich reaction with 3-pentanone afforded the products in
75/25 to 34/66 syn:anti diastereomeric ratios (Table 2, Entries 9-
14). When using 2-pentanone as the substrate, both electron-
withdrawing and -donating groups on benzaldehydes or anilines
had lesser effect on the yield, and all afforded the Mannich
products in ideal yields (Table 2, Entries 15-19). In contrast,
aldehydes with electron-donating groups and aromatic amines
treated with cyclohexanone afforded β-amino ketones in moderate
to good yields and decent diastereoselectivities (Table 2, Entries
20 and 21). To our delight, using acetophenone as the ketone, 85-
96% yields were achieved under the same condition for 4-11 h
at 50 °C (Table 2, Entries 22-25). When 2-pentanone and acetol
were used as the substrate, high regioselectivity more than 99:1
was obtained. To summarize, the transformation is applicable to a
variety of ketones and is more general than the existing protocols.
To understand the coordination chemistry of the cooperative
catalyst system, the interaction of [Cp2TiCl2] and p-aminophenol
was studied by 1H NMR experiments. To mimic the catalyst
system, 1.0 equiv of [Cp2TiCl2] and 2.0 equiv of p-aminophenol
were mixed in d6-DMSO-d6. The characteristic cyclopentadienyl
(Cp) protons could be regarded as a probe to measure the formation
of new titanocene complexes. Two characteristic Cp resonance
13d o-Cl
C2H5 CH3
C2H5 CH3
14d o-OCH3
15d o-Cl
C3H7
C3H7
C3H7
C3H7
C3H7
-(CH2)4-
-(CH2)4-
Ph
Ph
H
H
H
H
H
16d o-OCH3
17d p-OCH3
18d
19d
H
H
20e o-OCH3
21e
22e
H
H
<1:99
none
none
none
none
H
H
H
H
23f o-OCH3
24f
25f
H
H
aAldehyde, 1.0 mmol; aniline, 1.1 mmol; ketone, 27.1 mmol; [Cp2-
TiCl2], 0.05 mmol, p-aminophenol, 0.10mmol; 25 °C; 2 h. bIsolated
yields. cAldehyde, 1.0 mmol; aniline, 1.1 mmol; ketone, 27.1mmol;
d
[Cp2TiCl2], 0.05 mmol, p-aminophenol, 0.10 mmol; 50 °C; 2 h. Alde-
hyde, 1.0 mmol; aniline, 1.1 mmol; ketone, 1.5 mmol; [Cp2TiCl2], 0.05
mmol, p-aminophenol, 0.10mmol; 50 °C; 2 h. eAldehyde, 1.0 mmol;
aniline, 1.1 mmol; ketone, 1.5 mmol; [Cp2TiCl2], 0.05 mmol, p-
aminophenol, 0.10 mmol; 50 °C; 4 h. fAldehyde, 1.0 mmol; aniline,
1.1 mmol; ketone, 1.5 mmol; [Cp2TiCl2], 0.05 mmol, p-aminophenol,
g
1
0.10 mmol; 50 °C; 11 h. Determined by H NMR.
1
signals were observed by H NMR spectroscopy (Figure 2). The
Cp proton of titanocene dichloride I was at 6.69 ppm, and a
putative titanocene II was at 6.46 ppm. We found that the Cp
resonance of II increased while the resonance of I decreased
gradually. Finally, the relative integration intensities of titanocene
II and titanocene dichloride I remained stable. To investigate the
cooperation between the titanocene center and substrate, such as
Figure 2. 1H NMR experiments of 1.0 equiv of [Cp2TiCl2] and
2.0 equiv of p-aminophenol.
I: [Cp2TiCl2],
II: [Cp2Ti(η1-
NH2C6H4OH)2].
Chem. Lett. 2014, 43, 1832–1834 | doi:10.1246/cl.140705
© 2014 The Chemical Society of Japan | 1833

Figure 3. Proposed mechanism of [Cp2TiCl2]/p-aminophenol-catalyzed direct Mannich reaction.
acetone, benzaldehyde, or aniline, three more 1H NMR experiments
were performed. The results showed that there was no interaction
between each substrate and titanocene dichloride (See the
Supporting Information). These observations illustrated the coor-
dination between titanocene and p-aminophenol. More impor-
proceeded smoothly under mild conditions. [Cp2Ti(η1-NH2C6H4-
OH)2] (II) was regarded as a catalytic active species via H NMR
analysis and control experiments. Determination of the crystal
structure of the catalytic active species and further application to
more classic organic reactions are under way.
1
1
tantly, the new titanocene species was characterized by H NMR,
which exhibited the coordination of titanocene with the oxygen
atom of p-aminophenol tuning the Lewis acidity of titanocene.
(See the Supporting Information). Compared with that of the bis-
salicylato titanocene species,7 the chemical shift of [Cp2Ti(η1-
NH2C6H4OH)2] was lower in 1H NMR. Moreover, the electron
density of the titanocene center decreased, leading to the weaken-
ing of the Lewis acidity of the titanium center. These experiments
clearly demonstrated that the Lewis acidity of titanocene dichloride
can be adjusted successfully by exploiting different o-ligands. The
new titanocene species exhibits satisfactory catalytic activities for
the Mannich reaction with acetone and its derivatives.
This work was supported by the 111 Project (No. B14041), the
National Natural Science Foundation of China (Nos. 21271124,
21371112, and 21171112), the Fundamental Research Funds for
the Central Universities (No. GK201302015), the Doctoral Fund
of the Ministry of Education of China (No. 20120202120005) and
Natural Science Basic Research Plan in the Shaanxi Province of
China (No. 2012JM2006). We also thank Prof. J. Xiao and Prof.
C. Wang for useful discussions.
Supporting Information is available electronically on J-STAGE.
References
A proposed cooperative catalytic cycle is outlined in Figure 3.
Titanocene dichloride I as a precatalyst is coordinated by p-
aminophenol and transformed into catalyst II. In transition state A,
the incoming ketone is deprotonated and then the generation of
titanium enolate is accelerated as the carbonyl coordinates to
oxophilic Ti. Then, Brønsted acid activated condensation leads to
the formation of imine from aldehyde and aniline, which is treated
as an electrophile in the Mannich reaction.8 The key step of carbon-
carbon bond formation is illustrated in transition state B. Then the
coordinated enolate undergoes addition to the imine, which is
activated by hydrogen bonding from the amino group. This tran-
sition state showcases the cooperative nature of the new catalysis
system. Once the product is released, titanocene II is formed.
In conclusion, a new cooperative catalysis system featuring
the synergistic effect of organometallic Lewis acids and Brønsted
acid-base ligands was developed for highly efficient Mannich
reactions with aliphatic and aromatic ketones. The catalysis system
successfully catalyzed the direct three-component Mannich reac-
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in excellent yields. A mechanistic study strongly supports a dual
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1834 | Chem. Lett. 2014, 43, 1832–1834 | doi:10.1246/cl.140705
© 2014 The Chemical Society of Japan