Solvent strategy for unleashing the Lewis acidity of titanocene dichloride for rapid Mannich reactions

Article abstract of DOI:10.1039/c5ra27094d

The remarkable activation effect of alcohol solvent on kinetically inert titanocene dichloride was found to promote rapid three-component Mannich reactions. NMR and ESI-MS analyses as well as a control experiment of catalytic active species elucidated that the coordination of MeOH to the titanocene moiety unleashed the Lewis acid [Cp₂Ti(OMe)₂] and Br?nsted acid HCl, which led to the enhanced catalytic activity of [Cp₂TiCl₂].

Full text of DOI:10.1039/c5ra27094d

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Solvent Strategy for Unleashing Lewis Acidity of Titanocene
Dichloride for Rapid Mannich Reactions
Ya Wu,a, b Xiu Wang,a Yanlong Luo,a Jing Wang,a Yajun Jian,a Huaming Sun,a Guofang Zhang,a
Weiqiang Zhang,*a and Ziwei Gao*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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The remarkable activation effect of alcohol solvent on kinetically proved to be promising Lewis acid catalyst precursors7 due to its
inert titanocene dichloride was found to promote rapid three- kinetic stability, electronic tunable metal center and intrinsic
component Mannich reactions. NMR and ESI-MS analyses as well metallic Lewis acidity.8 Usually, the titanocene Lewis acids were
as control experiment of catalytic active species eluciated that the obtained by introducing weakly coordinating anion ligands or
coordination of MeOH to titanocene moiety unleashed Lewis acid neutral
ligands. For
example,
titanocene
complexes
[Cp2Ti(OMe)2]and Brønsted acid HCl, which led to enhanced [Cp2Ti(HBcat)2],9 Cp2Ti[P(OEt)3]2,10 [Ti(Cp)2(H2O)2(CF3SO3)2],11 and
catalytic activity of [Cp2TiCl2].
[Ti(Cp)2(H2O)2(C8F17SO3)2]12 as potential organometallic Lewis acid
catalyst showed particularly activity for the transformation of
carbonyl compounds (Scheme 1 (a)). However, employment of
expensive silver salts or moisture-sensitive reagents or low yield
limited their further application in the activation of kinetically inert
titanocene complexes via ligands strategy. Therefore, developing a
solvent activation strategy for titanocene Lewis acids is still of high
significance.
Organometallic Lewis acids have been of fundamental interests in
homogenous catalysis due to their ubiquitous reactivity and
selectivity in classic organic transformations.1 In the organometallic
Lewis acid catalysis the ligand and solvent are two critical factors
determining the reaction efficiency.2 Despite ligand effect has
clearly demonstrated the significant role in the catalytic reaction
over the decades,3 sophisticated co-ligands are judiciously selected
to stabilize Lewis acid counterparts and the involved ligand
inevitably requires tedious multi-step syntheses.4 The other critical
factor is that solvent can direct unprecedented chemical reactivity
and selectivity in catalytic organic transformations owing to the fact
that the solvents to be introduced would be able to adjust steric
balance, tune coordination of metallic centre, and control
hydrolysis and condensation.5 For instance, Brønsted acidic solvents
provided a green and sustainable option for maximising the
productivity of the zinc reagent catalysed Biginelli reaction.5c Using
γ-valerolactone as the solvent led to significant increase in reaction
rate as well as product selectivity in acid catalysed of xylose into
furfural.6 In addition, it is much easier to investigate solvent effect
as various solvent are ready to be used. However, compared with
ligand effect, less attention is paid on solvent effect, so the detailed
mechanism information on how they affect reaction is still rare.
Group IVB metallocenes, especially, titanocenes have been
Recently, we have disclosed a type of titanocene complexes with
increasing Lewis acidity by the cooperative effect of salicylic acid
ligands. Our ongoing interest in titanocene Lewis acid catalysis
promoted us to investigate more efficient activation strategies of
the stable titanocene complexes.13 Considering facile substitution
reactions of alkoxy, acyloxy and hydroxyl with Cp2TiCl2 in ethanol,
THF and water,14 it was feasible to improve the activity of Cp2TiCl2
by the interaction of solvent with Ti moiety. The introduction of
suitable solvent can be advantageous to obtain titanocene Lewis
acid complexes. However, to the best of our knowledge, solvent
effect hasn’t been proposed to enhance catalytic activity of
titanocene Lewis acids.
Previous work
a.Key Laboratory of Applied Surface and Colloid Chemistry, MOE, School of
Chemistry and Chemical Engineering, Shaanxi Normal University Xi’an 710062
(China) Fax: +86-29-81530727. E-mail: zwgao@snnu.edu.cn
b.College of Chemistry and Chemical Engineering, Xi’an Shiyou University, Xi’an
710065, P. R. China
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/x0xx00000x
(a)
This work
(b)
Scheme 1 Approaches to titanocene Lewis acids
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In this paper, we introduced a solvent strategy for unleashing Table 1 The effect of alcohols on Cp2TiCl2 catalyzed Mannich
Lewis acid and Brønsted acid via activating titanocene dichloride for reaction.
Entrya Alcohol
pKa
Catalyst (mol %) Yield(%)b
rapid Mannich reactions (Scheme 1 (b)). Kinetically inert titanocene
dichloride showed a significant activation in alcohols and efficiently
catalyzed three-component Mannich of aldehydes, ketones and
amines. Mechanism study including NMR and ESI-MS analyses as
well as control experiment shed light on the effect of alcohols on
releasing Lewis acidity of titanocene dichloride along with Brønsted
acidity, which led to the dramatic catalytic performances. To the
best of our knowledge, this constitutes the first time that the
intrinsic property of solvent dictates the activation of stable Cp2TiCl2
in catalytic organic transformation. Furthermore, the discovery
provides a mild and efficient approach to conduct three-component
Mannich reaction.
15.17±0.10
15.24±0.10
15.24±0.10
15.31±0.20
15.24±0.10
15.38±0.29
14.13±0.10
13.68±0.20
14.36±0.10
15.31±0.20
15.17±0.10
15.17±0.10
1
MeOH
1
95
94
88
79
83
15
28
7
2
EtOH
1
3
n-PrOH
i-PrOH
1
4
1
5
n-BuOH
t-BuOH
(CH2OH)2
Glycerol
PhCH2OH
C6H11OH
MeOH
1
6
1
7
1
8
1
9
1
0
10
11
12
1
21
97
85
2
Mannich reactions have been developed as model reactions of
evaluating solvent effect on the catalytic performance of titanocene
dichloride becuase titanocene based catalyst was regarded to be
sensitive to Mannich reaction according to our reported research12-
13. We began to investigate the Mannich reaction of benzaldehyde
(1.0 mmol), aniline (1.1 mmol) and acetophenone (2.0 mmol) in the
presence of titanocene dichloride (1 mol %) in diverse solvent (0.5
mL) at 25oC. The results are demonstrated in Figure 1. The catalytic
activity of Cp2TiCl2 in the condensation reaction was greatly
influenced by solvent. Preliminarily, traditionally used solvent
CH2Cl2 was evaluated while Cp2TiCl2 was almost inert in CH2Cl2.
Non-polar solvents such as benzene and n-hexane were not helpful
for the Mannich reaction and gave only 18% and 6% yields after 0.5
h. THF and CHCl3 as polar solvent slightly accelerated the reaction
(32% and 12% yields, respectively). More polar solvents such as
DMSO and CH3CN were obviously active for Cp2TiCl2 catalysis. To
our surprise, the condensation reaction accelerated dramatically
when employing EtOH and furnished β-amino-carboxyl compound
in 94% yield. Moreover, when MeOH replacing EtOH, the activity of
Cp2TiCl2 was also enhanced slightly and the higher yield was
obtained with 95%. The observations demonstrated that alcohol
was a unique solvent and played an important role in the Cp2TiCl2
MeOH
0.5
aReaction conducted with 1.0 mmol of benzadehyde, 1.1 mmol of
aniline, and 2.0 mmol of acetophenone in 0.5 mL alcohol at 25 °C
for 0.5 h. bIsolated yields were obtained after purification by
column chromatography.
catalyzed Mannich reactions. Based on alcohols as a protic solvent,
water was also paralleled to evaluate the reaction efficiency in the
catalytic system. However, no product was detected. These results
indicated that the catalytic activity of Cp2TiCl2 couldn'
t be
contributed to solvent polarity or hydrogen-bonding interaction.
Various alcohols were further investigated to demonstrate the
pronounced accelerating effect on titanocene catalyzed Mannich
reactions (Table 1). In addition to MeOH and EtOH (entries 1 and 2),
n-PrOH and n-BuOH featuring longer carbon-chain structure were
also proved as a validated solvent (entries 3 and 5). Based on facile
substitution reactions of alkoxy groups with Cp2TiCl2 in alcohols,14 it
is probably because that the coordination between alcohols and
titanocene species results in enhancing Lewis acidity of Ti centre
and thus improving the catalytic efficiency. This hypothesis was
further supported by the Mannich reactions catalysed by Cp2TiCl2 in
sterically hindered alcohols such as i-PrOH, t-BuOH, PhCH2OH and
cyclohexanol (entries 4, 6, 9 and 10). Owing to the fact that the
sterical hindrance is disadvantageous to alcohols coordinating to
organometallic centre, the yields of the condensation dramatically
decreased and the reaction using t-BuOH only afforded 15% yield.
Not surprisingly, it was also found that polylols i.e. ethylene glycol
and glycerol suppressed the accelerating effect of short-chain
monohydroxy alcohols, leading to only 28% and 7% yields of the
Mannich reaction (entries 7 and 8) because titanocene dichlorde in
polylols readily formed a stable five-membered ring. On the other
hand, the pKa of the alcoholic solvent was considered because it
probably shed light on the propensity for acid catalysis. Despite low
pKa of ethylene glycol and glycerol, the reaction failed to afford
high yields. In a word, these results suggested it is a possibility that
the coordination between alcohols and Ti center played a key role
in unleashing Lewis acidity and improving catalytic activity of
titanocene complexes. Besides, the optimized condition was also
provided with 1 mol-% titanocene catalyst and 0.5 mL MeOH
solvent (entries 11 and 12).
95
91
Yield(%)
66
48
32
18
12
6
0
0
Solvent
These findings led us to the discovery of a new protocol for inert
titanocene dichloride by a solvent strategy accelerating the direct
Figure 1 Solvent effect on titanocene dichloride catalyzed three-
component reaction. a Yield of isolated product.
2 | J. Name., 2012, 00, 1-3
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three-component Mannich reaction. The scope and limitation of the under optimized conditions (Table 2, entries 13-25). The reaction
new solvent enhenced catalyst system were evaluated with a range outcome was not significantly affected by aliphatic ketones. The
of aldehydes, amines and aromatic and aliphatic ketones in the catalytic Mannich condensation of cyclohexanone with substituted
optimized conditions (Table 2). Substitutions on either anilines or benzaldehydes and anilines afforded the products (4m-p) in 72-88%
benzaldehydes have little impact on the activity of the titanocene yields, whereas open chain ketones including acetone, 3-pentanone
catalyst. Both electron-withdrawing and donating groups of and 2-pentanone afforded the desired Mannich bases in 68-91%
aromatic substrates proved to be very effective, affording the yield (4q-y). The strong electron-withdrawing groups such as nitro-
Mannich condensation products in good yields (entries 1-12, 74%- substituted arylimine reacted much more slowly with a relatively
96%). Amine with chloro (4b) or methoxy (4c) substituents and low yield. To our delight, the catalytic system showed good anti-
aldehydes with chloro (4d) or methoxy (4e) substituents in para selectivity for the direct three-component Mannich reactions. As
sites led to excellent results (85-96% yields) when acetopheone was shown in Table 2, the catalytic Mannich condensation of 3-chloro-
used (entries 2-5). Moreover, the steric effect of substituents does benzaldehyde, aniline and 3-pentanone afforded aliphatic
not obviously interfere with the catalytic efficiency of the Mannich aminoketone (4w) with 80/20 d.r. that was determined by 1H NMR
reaction. For instance, ortho-substituents 2-Cl and 2-OCH3 spectroscopy.15 The corresponding reactions with substitutions on
benzaldehyde (4f, 4l) and 2-Cl anilines (4k) condense with either anilines or benzaldehydes furnished the product with the
acetophone with more than 70% yields (entries 6, 12 and 11).
values of anti/syn varied from 56/44 (4t) to 80/20 (4w) (entries 13-
The alcohol accelerating [Cp2TiCl2] catalytic system was also 16 and 20-24).
successfully applied in the Mannich reactions of aliphatic ketones
Table 2 Cp2TiCl2 in MeOH accelerated catalytic Mannich reactions
Entrya R1
R2
R3,R4
Yield (%)b Anti/Sync
1
2
3
4
5
6
7
8
H
H
H
H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
4a, 95
4b, 95
4c, 85
4d, 96
4e, 88
4f, 74
4g, 75
4h, 81
4i, 90
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
p-CH3
p-Cl
H
H
H
p-OCH3
p-Cl
o-Cl
p-NO2
p-Cl
H
H
p-NO2 Ph, H
H
Figure 2 Partial 400MHz 1H NMR spectra (CD3OD) of a solution
9
p-OCH3Ph, H
containing Cp2TiCl2 with addition of aniline.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
H
H
H
o-Cl
H
p-NO2Ph, H
Ph, H
Ph, H
4j, 81
4k, 76
4l, 85
n.d.
n.d.
n.d.
74:26
68:32
61:39
66:34
n.d.
6.64 ppm I [Cp2TiCl2];
6.70 ppm II [Cp2Ti(OCH3)2]
o-OCH3
H
H
p-Cl
p-NO2
H
p-Cl
p-OCH3
H
p-CH3
p-NO2 (CH2)4
(CH2)4
4m, 88
4n, 81
4o, 85
4p, 72
4q, 71
4r, 68
4s, 79
4t, 85
4u, 91
4v, 82
4w, 81
4x, 83
4y, 77
H
H
H
H
H
H
(CH2)4
(CH2)4
CH3, H
CH3, H
CH3, H
C2H5, CH3
n.d.
n.d.
56:44
74:26
65:35
80:20
71:29
n.d.
H
H
p-OCH3 C2H5, CH3
p-Cl
H
C2H5, CH3
C2H5, CH3
C2H5, CH3
n-C3H7, H
p-Cl
p-OCH3 p-Cl
H
H
aReactions conducted with 1.0 mmol of aldehydes, 1.1 mmol of
amines, and 2.0 mmol of ketones in the presence of 0.01 mmol of
catalyst in 0.5 mL MeOH at 25°C. bIsolated yields were obtained
after purification by column chromatography. cDetermined by 1H
NMR analysis of crude products.
Scheme 2 The coordination of Cp2TiCl2 with MeOH unleashed Lewis
acidity and Brøsnted acidity by 1H NMR and ESI-MS
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To shed light on delicate accelerating effect of alcohols, the
interaction between Cp2TiCl2 and MeOH was further investigated by
1H NMR and ESI(+)-MS, which were considered as powerful
techniques to investigate the organometallic species.16 1H NMR
experiments were conducted using Cp2TiCl2 in CD3OD at intervals
with addition of aniline. The characteristic cyclopentadienyl (Cp)
protons could be regarded as a probe to measure the formation of
new titanocene complexes. In the 1H NMR spectrum only one
prominent Cp singlet ( ) of Cp2TiCl2 (I) was detected at δ 6.64 ppm
upon the addition of Cp2TiCl2 into CD3OD (Figure 2), indicating no
coordination happened. However, after 1.0 equiv. of aniline was
Table 3 The paralleled experimenta
Entry
Catalyst(mol %)
----
Yield(%)b
1c
2
0
HCl (2)
36
53
55
93
3
dCp2Ti(OCH3)2 (II) (1)
eCp2Ti(OCH3)2 (II) (1)
dCp2Ti(OCH3)2/HCl (1/2)
4
5
aReaction conducted with 1.0 mmol of benzadehyde, 1.1 mmol of
aniline, and 2.0 mmol of acetophenone at 25 °C for 0.5 h. b Isolated
yields were obtained after purification by column chromatography.
cWithout Cp2TiCl2 in 0.5 mL MeOH. dFormed in situ from Cp2TiCl2
(0.01 mmol) and Mg(OMe)2 (0.01 mmol) in MeOH (0.5 mL).
eObtained from a benzene solution of 1.0 equiv. Cp2TiCl2 with
dropwise addition of a mixture of 2.0 equiv. MeOH and 2.0 equiv.
triethylamine in benzene at 50 oC and removal of triethylamine
hydrochloride by filtration.
added in the above solution, one new Cp protons singlet (
)
appeared immediately at δ 6.70 ppm. Titanocene chloride (I) was
consumed gradually in CD3OD in the presence of base and
transformed to new titanocene species Cp2Ti(OCH3)2 (II) (Scheme 2),
as revealed by ESI-MS analysis, corresponds to the [II+H]+ signal at
m/z 241.0706. These observations suggest that the MeOH is not
just a medium to dissolve the sandwich complexes but also a
reactant involved in the process of activating Cp2TiCl2 via methoxy
groups binding to Cp2TiIV moiety. So it is reasonable to draw a
conclusion that in the Mannich reaction, pre-catalyst titanocene
dichloride readily converted into the detectable titanocene species
II, when methanol served as solvent. Comparing the chemical shifts
of Cp protons of the Ti species, (I) and (II), the truth that the signal
of (I) is downfiled shifted, indicating the lewis acidity order as II>I. In
addition, it was also found that II can readily decomposed as the
cationic titanocene moiety [Cp2TiOCH3]+ (III) by releasing one
methoxy ligand, verified by ESI(+)-MS spectrum (m/z 209.0445). The
cation III was more electrophilic and should be originated from
Cp2Ti(OCH3)2 (II).
OCH3
O
Ti
OCH3
R3
O
III
R4
H
R3
R4
A
Ph
Cl
CH3OH
OCH3
OCH3
N
Ti
HCl
Ti
+
CH3OH
Ph
Cl
BrØnsted acid
II
Lewis acid
I
OCH3
Ph
Ti
HCl
Ph
N
O
Ph
R3
NH
O
R4
Dual activation
Ph
R3
To further elucidate the catalysis mechanism and figure out the
true catalysis species, a series of paralleled experiments were
conducted under the same conditions as the original protocol.
Above NMR and MS experiments show that Cp2Ti(OCH3)2 (II) was
produced, and an equivalent amount of HCl should be released
simultaneously. Although it is not easy to verify the existence of HCl
directly, its formation can be rationalized by the NMR experiment
that addition of organic base aniline assured the occurrence of
methoxylation of Cp2TiCl2. Thus it is of great significance to shed
light on the function of Cp2Ti(OCH3)2 (II) and HCl of the original
reaction. As Bronsted acids are prevalent catalysts for Mannich
reaction, HCl was primarily investigated, however, only 36% yield of
product was isolated (Table 3, entry 2). Next, we evaluated the
Cp2Ti(OCH3)2 (II) species, which was prepared following two
literature procedures. 17 We found that Cp2Ti(OCH3)2 could catalyze
the reaction, but not as efficient as the original protocol, because
the reaction yields are only 53% and 55% (Table 3, entries 3 and 4),
respectively. However, adding a MeOH solution of HCl to entry 3,
the condensation afforded an isolated yield of 93% (entry 5). It is
clear that the high efficiency of the condensation shouldn’t be
attributed to Brønsted acid or titanocene Lewis acid sole.
Conversely, we proposed that the co-involvement of the binary
acids, Cp2Ti(OCH3)2 and HCl, resulted in the perfect coupling
efficiency. This hypothesis are also in accordance with Yamamoto’s
binary acid principles.18 To sum up, the acceleration effect should
result from the cooperative effect of Lewis acid and Brønsted acid
released by Cp2TiCl2 in MeOH in situ.
R4
B
Scheme 3 Proposed mechanism of binary acid catalysis by MeOH
strategy of activating titanocene dichloride in Mannich reactions
Taken NMR, MS and paralleled experiments together, a catalytic
cycle via MeOH activation strategy for activating titanocene
dichloride in Mannich reactions is proposed and listed in Scheme 3.
Under the involvement of aniline, titanocene dichloride pre-catalyst
is activated by MeOH to give titanocene dimethoxy complexes II
and releases HCl simultaneously. The newly formed complex II is
liable to release one methoxy ligand yielding the cation III which is
prone to coordinate with ketone generates intermediate. In
intermediate A, the enolization is accelerated synergistically as the
carbonyl coordinate to oxophilic Ti and the leaving methoxy ligand
abstracts the proton. The coordinated enolate then undergoes
addition to the aldimine which is activated by protonation with the
released HCl and Ti centre of III.19 The carbon-carbon bond
formation as a key step is illustrated in 6-membered transition state
B proposed in its chair conformation. This transition state B
showcases the cooperative nature of this binary acid system
unleashed by titanocene dichloride in MeOH. A critical examination
of the diastereomeric outcome from the reactions corresponding to
entries 13-16 and 20-24 in Table 2 should provide significant insight
4 | J. Name., 2012, 00, 1-3
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In summary,
a
solvent strategy for improving inert
organometallic complexes catalysis for rapid three-component
Mannich reaction was developed. Mechanism study including NMR
and ESI(+)-MS analyses as well as control experiment elucidated the
effect of alcohols on the dramatic catalytic performances of
titanocene dichloride for the condensation. The investigation of
titanocene dichloride in MeOH has provided compelling evidence
9
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10 T. K. Hollis, N. P. Robinson and B. Bosnich, Organometallics,
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2012, 18, 6172.
along with Brønsted acid, leading to cooperatively enhanced
catalytic activity. Additionally, the new catalyst system allows for
mild and rapid three-component Mannich reactions with aromatic
and aliphatic substrate scopes.
12 Y. Wu, C. Chen, G. Jia, X. Zhu, H. Sun, G. Zhang, W. Zhang and Z.
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Acknowledgements
This work was supported by the 111 Project (B14041), the grant
from National Natural Science Foundation of China (21571121,
21271124, 21272186), the Fundamental Funds Research for the
Central Universities (No. GK201501005), the Program for
Changjiang Scholars and Innovative Research Team in University
(IRT_14R33) and Natural Science Basic Research Plan in Shaanxi
Province of China (2012JM2006).
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DOI: 10.1039/C5RA27094D
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