Asymmetric Michael addition reactions catalyzed by calix[4]thiourea cyclohexanediamine derivatives

Article abstract of DOI:10.3762/bjoc.14.164

A number of upper rim-functionalized calix[4]thiourea cyclohexanediamine derivatives have been designed, synthesized and used as catalysts for enantioselective Michael addition reactions between nitroolefins and acetylacetone. The optimal catalyst 2 with

Full text of DOI:10.3762/bjoc.14.164

Asymmetric Michael addition reactions catalyzed by
calix[4]thiourea cyclohexanediamine derivatives
Zheng-Yi Li1, Hong-Xiao Tong1, Yuan Chen1,2, Hong-Kui Su1, Tangxin Xiao*1,
Xiao-Qiang Sun1 and Leyong Wang*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1901–1907.
1Jiangsu Province Key Laboratory of Fine Petrochemical Engineering,
School of Petrochemical Engineering, Changzhou University,
Changzhou 213164, China and 2Key Laboratory of Mesoscopic
Chemistry of MOE, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210023, China
doi:10.3762/bjoc.14.164
Received: 14 April 2018
Accepted: 29 June 2018
Published: 25 July 2018
Email:
This article is part of the thematic issue "Macrocyclic and supramolecular
chemistry".
Tangxin Xiao* - xiaotangxin@cczu.edu.cn; Leyong Wang* -
lywang@nju.edu.cn
Guest Editor: M.-X. Wang
* Corresponding author
© 2018 Li et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
asymmetric Michael addition reaction; calix[4]arene;
cyclohexanediamine; thiourea
Abstract
A number of upper rim-functionalized calix[4]thiourea cyclohexanediamine derivatives have been designed, synthesized and used
as catalysts for enantioselective Michael addition reactions between nitroolefins and acetylacetone. The optimal catalyst 2 with a
mono-thiourea group exhibited good performance in the presence of water/toluene (v/v = 1:2). Under the optimal reaction condi-
tions, high yields of up to 99% and moderate to good enantioselectivities up to 94% ee were achieved. Detailed experiments clearly
showed that the upper rim-functionalized hydrophobic calixarene scaffold played an important role in cooperation with the catalyt-
ic center to the good reactivities and enantioselectivities.
Introduction
During the past decades, asymmetric organocatalysis has played chiral nitro carbonyl compounds, such as bioactive agrochemi-
an important role as a tool for the syntheses of chiral molecules cals and drugs [7,8]. Although great progress has been made in
under mild conditions [1-4]. Among these reactions, the asym- this research field, it is still need of further effort to synthesize
metric Michael reaction is a powerful strategy to construct new efficient chiral organic catalysts for this kind of Michael
versatile intermediates due to its synthetic convenience and reactions.
good stereoselectivity [5,6]. Accordingly, different versions of
this reaction have been extensively studied. Notably, the The thiourea functional group has played a critical role in
Michael addition reaction of 1,3-dicarbonyl compounds to organocatalysis due to its ability in forming hydrogen bonds
conjugated nitroalkenes is very important for the synthesis of with substrates. This may lead to activated forms of the sub-
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Beilstein J. Org. Chem. 2018, 14, 1901–1907.
strates allowing the corresponding reaction to occur [9-11]. For excellent enantioselectivity [35]. As part of our ongoing studies
example, Jacobsen and co-workers pioneered an effective chiral to develop novel types of organocatalysts for asymmetric catal-
thiourea catalyst which was employed in an asymmetric ysis, in this study, we aimed to synthesize novel upper rim-
Strecker reaction [12,13]. In 2016, Hernández-Rodríguez and functionalized calix[4]thiourea cyclohexanediamine derivatives
co-workers reported the preparation of bifunctional thioureas to catalyze asymmetric Michael addition reactions of acetylace-
that contained either a methyl or trifluoromethyl group [14]. tone and aromatic nitroalkenes.
They discovered that the employment of chiral moieties with an
Results and Discussion
α-trifluoromethyl group in thioureas show a positive effect on
the selectivity and yields of the Michael reactions.
Synthesis of catalysts
The chemical structures and synthetic pathways for catalysts are
Supramolecular catalysis has drawn tremendous interest in the shown in Scheme 1 and Scheme 2, respectively. A series of
past few years [15-23]. In this context, calixarenes are ideal upper rim-functionalized calix[4]arene-based cyclohexanedi-
supramolecular macrocyclic scaffolds for the design of molecu- amine derivatives 1–3 have been prepared. Calix[4]arene deriv-
lar receptors and organocatalysts due to their unique and ative 5 with an amino group on the upper rim was first pre-
tunable molecular architecture together with the ease of func- pared according to a literature report [38]. Then, the amino
tionalization on the lower and upper rims [24-28]. Interestingly, group was converted to an isothiocyano group through reaction
their hydrophobic cavity also exhibits phase transfer catalytic with phenyl chlorothionocarbonate under alkaline conditions to
function [29]. By attaching different pendants with catalytic obtain compound 6. Subsequently, different chiral cyclohexane-
ability to the scaffolds, this may offer us the opportunity to diamine derivatives were reacted with calix[4]arene-based com-
improve the green aspect of many reactions both in organic and pound 6 to form the corresponding substituted thioureas. By this
aqueous medium [30]. For example, it has been reported that route the monosubstituted primary amine 1, monosubstituted
calixarenes linked with thiourea groups can be used to catalyze tertiary amine 2 and disubstituted tertiary amine 3, respectively,
asymmetric Aldol reactions or Michael addition reactions in were obtained. Of note, for the preparation of compound 1 the
recent years [31-33]. Compared with the lower rim in the cone chiral mono-Boc-protected cyclohexanediamine was used for
conformation of calixarenes, the functionalization of the upper the coupling reaction. The protecting group was removed by
rim is more challenging. Notably, it should be more valuable to treatment with CF3COOH to afford 1. Moreover, in order to
exploit the cavity of upper rim-functionalized calixarenes comparatively study the role of the cavity of calix[4]arene, we
because of the possibility of simultaneously using the hydro- also synthesized a model catalyst 4 by a similar synthetic proce-
phobic cavity and chiral sites during a catalytic process [24,25]. dure as outlined for catalyst 2. All compounds 1–4 were fully
characterized by NMR spectroscopy and HRMS analyses.
Recently, we have reported a series of different functionalized
organic catalysts based on calixarenes [26,34-38]. For example, Optimization of reaction conditions
we have been developed a calix[4]arene-based L-proline cata- Generally, conjugate additions were employed for evaluating
lyst able to catalyze aldol reactions in aqueous solution with the catalytic activities of the new chiral amino-substituted
Scheme 1: Catalysts synthesized and screened in this study.
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Beilstein J. Org. Chem. 2018, 14, 1901–1907.
Scheme 2: Synthetic routes for organocatalysts 1–4.
thioureas [33,39]. For this, the Michael addition reaction of ace- organocatalysts (Table 1, entries 1–4). From Table 1, it can be
tylacetone (8) to β-nitrostyrene (7a) was chosen as the model seen that the yield with using the model catalyst 4 (only 75%) is
reaction to evaluate the efficiency of compounds 1–4 as chiral significantly lower than those obtained with catalysts 1–3 in
Table 1: Screening of catalysts and solvents.a
entry
catalyst
solvent
time (h)
yieldb (%)
eec (%)
1
2
1
2
3
4
2
2
2
2
2
2
2
2
2
2
H2O
H2O
1
96
99
99
75
62
29
26
23
17
56
37
67
80
13
6
1
41
42
28
90
53
23
23
26
77
58
68
50
70
3
H2O
1
4
H2O
6
5
toluene
CH3CN
DMF
48
48
48
48
48
48
48
48
48
48
6
7
8
DMSO
1,4-dioxane
THF
9
10
11
12
13
14
CH2Cl2
Et2O
n-hexane
neat
aReagents and conditions: catalyst (2 mol %), nitrostyrene (0.5 mmol), and acetylacetone (1 mmol), solvent (0.5 mL), rt; bisolated yields; cdetermined
by chiral HPLC analysis.
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Beilstein J. Org. Chem. 2018, 14, 1901–1907.
water (96–99%). Moreover, the reaction time using catalyst 4 ever, no improvements could be achieved (Table 2, entries 7
was 6 h which is much longer compared to 1 h needed in case and 8). To our delight, increasing the catalyst loading of 2 from
of catalysts 1–3. These results showed that the catalysts com- 2 mol % to 5 mol % resulted in a significant improvement in
prising the calix[4]arene cavity are superior to the model cata- enantioselectivity (94% ee; Table 2, entry 9). However, further
lyst in terms of catalytic reactivity. This is likely due to the for- increasing the catalyst loading led to a slight decrease in enan-
mation of multiple microreactors at the water molecules’ inter- tioselectivity (Table 2, entry 10). Based on the above screening,
face, with the calix[4]arene hydrophobic cavity attracting reac- the best results were obtained with 5 mol % of 2 in a mixed sol-
tants and accelerating the reaction [35,40]. The primary amine- vent of toluene and water (v/v = 2:1) at room temperature.
containing catalyst 1 showed poor performance compared to the
corresponding tertiary-amine containing catalysts 2 and 3. Al- The scope of reaction substrates
though catalysts 2 and 3 demonstrated similar reactivities, we With the optimal reaction conditions in hand, a set of aryl
chose monosubstituted catalyst 2 as catalyst for further optimi- nitroolefins 7a–k was then employed to explore the generality
zation according to the principle of atomic economy.
of this protocol and the results are summarized in Figure 1. All
nitroolefins reacted smoothly with acetylacetone (8) to afford
Next, the effect of solvents on the reaction catalyzed by 2 was the corresponding products 9a–k in high yields (90–99%) and
investigated and the results are summarized in Table 1. The moderate enantioselectivities for 9b–k (46–76% ee). In case of
results revealed that both the yield and the enantioselectivity 9a an excellent enantioselectivity (94% ee) was obtained. This
were highly dependent on the solvents. Poor yields, lower enan- might be due to the fact that the nitrostyrene 7a lacking substit-
tioselectivities and long reaction time (48 h) were observed uents has minimal steric hindrance and tends to bind with the
when the reactions were performed in organic solvents or with- calixarene cavity by supramolecular host–guest interactions
out any solvent (Table 1, entries 6–14). Interestingly, using tol- which could further improve the enantioselectivity. In addition,
uene as the solvent afforded a higher enantioselectivity electronic effects of the substituents on the aromatic ring
(90% ee) with a low yield (62%, Table 1, entry 5), while H2O showed a significant influence on the reaction. The presence of
as the solvent gave higher yields (99% yield) with poor enantio- a strong electron-withdrawing trifluoromethyl group afforded
selectivity (41% ee, Table 1, entry 2).
the product 9e (76% ee) with higher enantioselectivity than a
strong-electron donating methoxy group (9c, 46% ee), while
Therefore, in order to get good yield and enantioselectivity at products with methyl and halogen groups showed moderate en-
the same time, a mixed solvent of toluene and water was chosen antioselectivities (59–72% ee). For the same substituent at dif-
for the reaction (Table 2). The results showed that a good yield ferent positions of the aromatic ring, it can be seen that in case
and enantioselectivity could be obtained when the volume ratio of the electron-donating methoxy group the position of the sub-
of toluene to water was 2:1 (Table 2, entry 5). We tried to stituent has a remarkable effect on the enantioselectivity (meta:
further improve the catalytic effect by decreasing the reaction 63% ee, para: 46% ee). However, no obvious trends could be
temperature and increasing the amount of acetylacetone. How- observed in case of ortho- or para-halogenated substrates.
Table 2: Optimization of reaction conditions.a
entry
toluene/H2O (v/v)
time (h)
yieldb (%)
eec (%)
1
2
1:1
1:2
1:3
1:5
2:1
3:1
2:1
2:1
2:1
2:1
5
5
99
99
99
99
99
63
47
78
99
99
68
70
63
54
75
76
74
63
94
92
3
3
4
1
5
5
6
36
40
7
7d
8e
9f
10g
4
4
aReagents and conditions: catalyst 2 (2 mol %), nitrostyrene (0.5 mmol), and acetylacetone (1 mmol), toluene and water (0.48 mL), rt; bisolated yields;
cdetermined by chiral HPLC analysis; dreaction performed at 0 °C; e2.5 mmol acetylacetone used; f5 mol % catalyst 2 used; g10 mol % catalyst 2
used.
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Beilstein J. Org. Chem. 2018, 14, 1901–1907.
Figure 1: Asymmetric Michael addition of acetylacetone with different nitroolefins catalyzed by organocatalyst 2. Reagents and conditions: catalyst 2
(5 mol %), nitroolefin (0.5 mmol), acetylacetone (1 mmol), toluene (0.32 mL) and water (0.16 mL), rt.
Mechanism study
group through double hydrogen bonding. Based on the better
There are two possibilities for the bifunctional thiourea-cata- enantioselectivity observed for product 9a over 9b–k, it was
lyzed asymmetric Michael addition reaction mechanism as has deduced that the binding of the nitroolefin with the calixarene
been summarized by Wang and co-worker [41]. In case of 1,3- cavity might be affected by the steric hindrance of the groups
dicarbonyl compounds or nitroolefins as substrates in the reac- present on the aromatic ring. We propose the following plau-
tion, the question arises, which one is activated by the thiourea sible synergistic catalytic mechanism (Scheme 3). First, the two
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Beilstein J. Org. Chem. 2018, 14, 1901–1907.
Scheme 3: Possible proposed reaction mechanism.
oxygen atoms of the nitro group in the nitrostyrene are acti- catalyst 2 played an important role in controlling reaction activ-
vated through double hydrogen bonding with the thiourea ities and enantioselectivities.
group, while the benzene ring is held by a supramolecular
host–guest interaction with the calixarene to form a stable tran-
Supporting Information
sition state A. Then, another hydrogen bond is formed between
the nitrogen atom of the tertiary amine group in A and acetyl-
Supporting Information File 1
acetone in its enol form, leading to the formation of a ternary
complex B. Finally, nucleophilic attack of acetylacetone on the
nitrostyrene creates a new C–C bond forming binary complex C
from which the enantioselective product is released.
Experimental procedures, characterization data for all
compounds and copies of NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-164-S1.pdf]
Conclusion
In summary, we have synthesized a series of upper rim-functio-
nalized calix[4]arene-based chiral cyclohexanediamine thiourea
catalysts 1–3 and tested as organocatalysts for the enantioselec-
tive Michael reactions of nitroolefins to 1,3-dicarbonyl com-
pounds. Under the optimal conditions, catalyst 2 smoothly cata-
lyzed the reactions in mixed solvent of toluene and water
(v/v = 2:1) at room temperature to afford the products in high
yields (90–99%) and with moderate to good enantioselectivities
(46–94% ee). By comparing with model catalyst 4, the
calixarene scaffold, especially its hydrophobic cavity present in
Acknowledgements
We gratefully acknowledge the financial support of the National
Natural Science Foundation of China (Nos. 21572026 and
21702020), the Natural Science Foundation of Jiangsu Colleges
and Universities (14KJA150002), Jiangsu Key Laboratory of
Advanced Catalytic Materials and Technology (BM2012110),
Advanced Catalysis and Green Manufacturing Collaborative
Innovation Center (ACGM2016-06-05), and the Priority Aca-
demic Program Development of Jiangsu Higher Education
Institutions.
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Beilstein J. Org. Chem. 2018, 14, 1901–1907.
25.Gutsche, C. D. Acc. Chem. Res. 2002, 16, 161–170.
ORCID® iDs
Zheng-Yi Li - https://orcid.org/0000-0001-9653-0687
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26.Li, Z.-Y.; Chen, J.-W.; Liu, Y.; Xia, W.; Wang, L. Curr. Org. Chem.
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Polycyclic Aromat. Compd. 2018, 38, 168–179.
Tangxin Xiao - https://orcid.org/0000-0002-2864-9587
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