Glucose-containing imidazolium salt-catalyzed cross-aldol reaction of isatins and unactivated ketones

Article abstract of DOI:10.1007/s11164-017-3246-3

Ketone–ketone cross-aldol reaction of isatins and unactivated ketones was catalyzed by glucose-containing imidazolium salt β-1-imidazole-2,3,4,6-tetra-o-hydroxy-d-glucopyranosyl bromide in neutral condition to generate 3-alkyl-3-hydroxyindolin-2-ones in e

Full text of DOI:10.1007/s11164-017-3246-3

Res Chem Intermed
https://doi.org/10.1007/s11164-017-3246-3
Glucose-containing imidazolium salt-catalyzed cross-
aldol reaction of isatins and unactivated ketones
Yu Wan2 Rui Yuan2 Hao Cui1 Xiao-xiao Zhang1
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Ming-qi Li1 Jiang-biao Xu1 Peng-fei Dou1 Long-yan Zhang1
Hui Wu1,2
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Received: 27 June 2017 / Accepted: 29 December 2017
Ó Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract Ketone–ketone cross-aldol reaction of isatins and unactivated ketones
was catalyzed by glucose-containing imidazolium salt b-1-imidazole-2,3,4,6-tetra-
O-hydroxy-D-glucopyranosyl bromide in neutral condition to generate 3-alkyl-3-
hydroxyindolin-2-ones in excellent yield.
Keywords Glucose-containing imidazolium salt Á Noncovalent catalyst Á
Unactivated ketone–ketone cross-aldol reaction
Introduction
The aldol reaction has drawn much attention for several decades because it is a very
important protocol to form carbon–carbon bonds [1–5]. Moreover, it affords b-
hydroxyl carbonyl compounds as versatile synthetic motifs of many biologically
and pharmaceutically important intermediates [6–9].
Compared with normal ketones, isatins are relatively stronger H-bond acceptors
[10–12], which makes them good substrates for various organic, e.g., condensation,
Yu Wan and Rui Yuan contributed equally to this work.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11164-
017-3246-3) contains supplementary material, which is available to authorized users.
&
Hui Wu
wuhui72@aliyun.com
1
2
School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou 221116,
People’s Republic of China
Key Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Jiangsu Normal
University, Xuzhou 221116, People’s Republic of China
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Y. Wan et al.
reactions. The products generally contain a quaternary carbon at C3-position, and
this skeleton is widely found in natural products that show interesting biological
activities [13–15].
Recently, cross-aldol reaction of isatins with unactivated ketones has gradually
aroused our interest. Various catalysts have been used to improve the reaction.
Application of amino acids or peptides in the reaction was reported successively.
Tomasini’s [16] and Bunge’s group [17] used dipeptide and pseudopeptide as
ˆ
catalyst, respectively. Correa [18] reported the enantioselective aldol reaction of
isatin with acetone catalyzed by L-proline, and Xie [19] reported the reaction of a,b-
unsaturated ketones with isatin catalyzed by arginine. Although amino acids and
peptides gave good yield and stereoselectivity, the reaction was very slow
(2–6 days). Instead, many studies used amino acid derivatives, such as leucinol
[9, 20], 2-(diphenylhydroxymethyl)pyrrolidine [21], amino amides [22–27], and
amino acid sulfonamide [28], as catalyst, but this could not shorten the reaction time
significantly. Quinidine thiourea [29, 30] and quinidine urea [31] performed well
when used to catalyze the reaction of activated ketones such as acetylphosphonate,
3-acetyl-2H-chromen-2-ones or 2,2-difluoro-1,3-diketones with isatins, but the
direct aldol reactions of unactivated ketones with isatins were very slow (3–7 days)
when catalyzed by quinidine thiourea, binaphthyl-modified catalyst, or carbohy-
drate-derived thiourea [32–34]. The reaction of cycloketones and isatin was also
studied; when using cyclohexanediamine as catalyst, the reaction could not proceed
smoothly without cocatalyst [35], and when using biaryl-based bifunctional
catalysts, the substrate scope was narrow [36]. 1,4-Diazabicyclo[2.2.2]octane
(DABCO) showed good catalytic activity, but unfortunately the substrates were
limited to acetophenones [37].
Recently, we found that glucose-containing imidazolium salts and glucose-
containing pyridine salts showed high catalytic activity [38–40]. Herein, based on
earlier research, we investigated the catalytic capability of glucose-containing
imidazolium salts (Scheme 1) in ketone–ketone cross-aldol reactions of isatins and
unactivated ketones. The results indicated that some of them could act as efficient
catalysts for this reaction in neutral condition without any cocatalyst.
Results and discussion
General procedures and apparatus are shown in the Electronic Supporting
Information.
The structure of glucose-containing imidazolium salts 3–8 was determined by
infrared (IR), and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The
1H NMR spectrum of compound 3 exhibited a double peak at d = 6.05 ppm
(J = 8.4 Hz) for the C1–H. Comparing with the literature value [41], it is clear that
the imidazole ring was seated in the equatorial bond of C1 (Fig. 1) and compounds 3
and 6 (J = 8.8 Hz) had b-configuration.
The pH value of compounds 3–8 was then measured to evaluate their catalytic
potential (Table 1). According to Table 1, the pH value varied considerably
(1.44–10.09), influenced by the groups on the glucose ring. At the same
123

Glucose-containing imidazolium salt-catalyzed cross-aldol…
Scheme 1 Synthesis of glucose-incorporated imidazoliums ([Bmim-G0]?[X]-)
concentration (10-2 mol L-1), compounds 3–5 (with acetyl on sugar ring)
displayed faint acidity while compounds 6, 7 displayed alkalescency. Compared
with them, compound 8 possessed strong acidity caused by four sulfonic acid
groups. These results show that some of them could be used as acid catalysts, while
others may be used as basic or neutral ones, indicating their wide potential for future
use in organic synthesis.
Subsequently, their catalytic effect was investigated in direct condensation of
isatin and acetophenone (Table 2, entries 1–6). It is interesting that only catalyst 6
(pH 10.09) could promote this reaction (Table 2, entry 4) with high yield (88 %).
Weak acid L-proline (Table 2, entry 7) and strong acids p-toluenesulfonic acid
(TsOH, Table 2, entry 8), Cl–SO3H (Table 2, entry 9), and trifluoroacetic acid
(TFA, Table 2, entry 10) proved useless. Strong base 1,8-diazabicyclo[5.4.0]undec-
123

Y. Wan et al.
Glucose
Glucose
Fig. 1 Coupling constant of C1–H in glucose [11] and compound 3
Table 1 pH of imidazolium
salts and other catalysts
Entry
Compound
pHa
1
2
3
4.63
3.67
4.10
10.09
9.12
1.44
6.40
1.84
1.44
1.62
8.54
12.15
4
3
5
4
6
5
7
6
8
7
L-Proline
TsOH
8
Measured by pH meter; working
solution (10-2 mol L-1) was
prepared by dissolving 10-3 mol
9
Cl–SO3H
TFA
10
catalyst in 5 mL deionized water 11
and diluting to 100.0 mL with
deionized water
N-Methylimidazole
DBU
12
7-ene (DBU) could also promote the reaction, but with lower yield compared with 6.
A possible reason is decomposition of isatin in strong alkali environment. These
results confirm the importance of proper acidity in this reaction. Moreover, N-
methylimidazole could not catalyze the reaction, highlighting the key role of the
glucose ring of catalyst 6 for the reaction. The effective amount of catalyst 6 was
20 mol%, and increasing the catalyst loading could not further enhance the product
yield (Entry 14).
The reaction conditions were then optimized based on the yield of 11a (Table 3).
According to Table 3, ethanol was the best solvent (entry 2), and the most
economical reaction time was 12 h (entry 14). The optimal temperature was 50 °C.
Therefore, 20 mol% 6 as catalyst in EtOH at 50 °C for 12 h was the optimum
reaction condition.
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Glucose-containing imidazolium salt-catalyzed cross-aldol…
Table 2 Screening of catalysts
Entry
Catalyst
X (mol%)
Yield (%)a
1
3
20
20
20
20
20
20
20
20
20
20
20
20
10
30
Nrb
Nrb
Nrb
88
Nrb
Nrb
Nrb
Nrb
Nrb
40
2
4
3
5
4
6
5
7
6
8
7
TFA
8
6 ? TFA (1:1)
9
L-Proline
10
11
12
13
14
6 ? L-proline (1:1)
DBU
75
Nrb
N-Methylimidazole
6
6
79
87
All reactions carried out at scale of 0.1 mmol isatin (9a) and 3.0 mmol acetophenone (10a) in 2 mL
ethanol at r.t. for 12 h
aIsolated yield
bNo reaction
To explore the application of this method, the scope of the substrate was
evaluated using a variety of isatins at the optimal condition (Table 4). Both
acetophenone and acetone could afford moderate to high yield, while acetone
bearing more active a-H atoms gave higher yield, indicating that the reaction was
cross-aldol condensation from a-H of ketone carbonyl to isatin. Higher yield and
faster reaction rate were obtained using isatins bearing electron-withdrawing groups
(Table 4, entries 2–4, 11, 12). A possible reason is that electron-withdrawing groups
increased the reactivity of the b-carbonyl, facilitating the reaction.
To further confirm the structure of the product 11, we cultivated the crystal of
11m and carried out X-ray diffraction analysis (Figs. 2, 3).
Catalyst recyclability was also investigated using synthesis of 11j (Table 5).
After completion, the solvent was evaporated and water was added. The aqueous
phase was extracted using CH2Cl2 (3 9 15 mL) to separate the catalyst and
product. The catalyst was recovered by concentration and drying the aqueous phase.
It was observed that the catalyst could be used for three times with minimal loss of
catalytic activity.
To determine the mechanism, catalyst 12 was synthesized from 1,2-dimethylim-
idazole instead of 1-methylimidazole. When the 2-position of imidazole ring was
123

Y. Wan et al.
Table 3 Screening of solvent, temperature, and time
Entry
Solvent
T (°C)
t (h)
Yield (%)a
1
H2O
R.t.
R.t.
R.t.
R.t.
R.t.
R.t.
R.t.
R.t.
R.t.
0
48
48
48
48
48
48
48
48
48
48
48
48
24
12
6
50
65
63
88
46
75
43
80
Nrb
68
Nrb
96
94
94
80
2
Et2O
3
THF
4
EtOH
5
CH2Cl2
CH3CN
Toluene
1,4-Dioxane
[BMIM][BF4]
EtOH
6
7
8
9
10
11
12
13
14
15
EtOH
-25
50
EtOH
EtOH
50
EtOH
50
EtOH
50
All reactions carried out at scale of 0.1 mmol isatin (9a) and 3.0 mmol acetophenone (10a) in 2 mL
ethanol
aIsolated yield
bNo reaction
substituted by CH3 (cat. 12), the yield dropped remarkably (Table 6), indicating that
the acidity of C–H in imidazole plays an important role.
The possible transition state in the formation of 11 is shown in Scheme 2. We
supposed that the product was generated from the synergistic effect of the enolate
anion A (blue) of ketone, isatin (green), and catalyst 6. We believe that the
imidazolium ion made the H at 2-position a better proton donor, and catalyst 6 may
play a dual role: acting as a proton donor to promote ketone to form enolate ion and
as a hydrogen-bond donor to bind with isatin.
123

Glucose-containing imidazolium salt-catalyzed cross-aldol…
Table 4 Synthesis of 11 under optimum conditions
Product
R1
R2
Yield (%)
11a
11b
11c
11d
11e
11f
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
90
88
96
95
87
85
80
76
70
99
97
97
85
87
73
5-F
5-Cl
5-Br
5-CH3
5-CH3O
5,7-(CH3)2
H
11g
11h
11i
5-F
CH3
11j
5-Cl
CH3
11k
11l
5-Br
CH3
5-NO2
5-CH3
5-CH3O
5,7-(CH3)2
CH3
11m
11n
11o
CH3
CH3
CH3
Fig. 2 Crystal structure of 11m
123

Y. Wan et al.
Fig. 3 Crystal packing diagram
of 11m
Table 5 Recyclability of
catalyst in synthesis of 11j
Cycle no.
Isolated yield (%)
1
2
3
4
99
90
78
56
Table 6 Control experiment
for synthesis of 11a
Catalyst
Isolated yield (%)
6
90
12
24.7
Scheme 2 Possible transition state
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Glucose-containing imidazolium salt-catalyzed cross-aldol…
Conclusions
We synthesized and used b-1-imidazole-2,3,4,6-tetrahydroxy-D-glucopyranosyl
bromide as catalyst in the cross-aldol reaction between unactivated ketones and
isatins. The reaction proceeded smoothly in neutral condition without any
cocatalyst. The substrate scope was broad, and the product could be obtained in
high yield. These results indicate that the catalyst can remarkably promote the cross-
aldol reaction and may be utilized for synthesis of biologically significant 3-alkyl-3-
hydroxyindolin-2-ones in industry.
Acknowledgements We are grateful to the foundation of the Priority Academic Program Development
of Jiangsu Higher Education Institutions, Major Project of Natural Science Research of University in
Jiangsu (nos. 14KJA430003, 15KJA180002), and Aid project for PhD faculties in Jiangsu Normal
University (17XLR023), for financial support.
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