Resin-immobilized pyrrolidine-based chiral organocatalysts for asymmetric Michael additions of ketones and aldehydes to nitroolefins

Article abstract of DOI:10.1039/c4ra10684a

Based on the electrostatic adsorption between acidic resins and organocatalysts, a series of resin-supported chiral organocatalysts were designed and synthesized. They were evaluated for the asymmetric Michael addition of cyclohexanone with nitrostyrene, in which, catalyst 3 (Fig. 1) exhibited the best catalytic performance. This reaction proceeded under catalyst 3 smoothly at room temperature without any solvent or additive and could give product with high yield (95%) and good stereoselectivity (90% ee, 98:2 dr). Encouragingly, catalyst 3 was easily isolated and reused for 16 consecutive runs without obvious loss of reaction enantioselectivity. Furthermore, it was successfully applied to catalyze the reactions of a series of ketones and aldehydes with nitroolefins.

Full text of DOI:10.1039/c4ra10684a

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Resin-immobilized pyrrolidine-based chiral
organocatalysts for asymmetric Michael additions
Cite this: RSC Adv., 2015, 5, 3461
of ketones and aldehydes to nitroolefins†
ab
Richeng Zhang,ab Guohui Yin,ab Yang Li,ab Xilong Yanab and Ligong Chen
*
Based on the electrostatic adsorption between acidic resins and organocatalysts, a series of resin-
supported chiral organocatalysts were designed and synthesized. They were evaluated for the
asymmetric Michael addition of cyclohexanone with nitrostyrene, in which, catalyst 3 (Fig. 1) exhibited
the best catalytic performance. This reaction proceeded under catalyst 3 smoothly at room temperature
without any solvent or additive and could give product with high yield (95%) and good stereoselectivity
(90% ee, 98 : 2 dr). Encouragingly, catalyst 3 was easily isolated and reused for 16 consecutive runs
without obvious loss of reaction enantioselectivity. Furthermore, it was successfully applied to catalyze
the reactions of a series of ketones and aldehydes with nitroolefins.
Received 19th September 2014
Accepted 5th December 2014
DOI: 10.1039/c4ra10684a
www.rsc.org/advances
Michael addition is one of the most important carbon–carbon
Thus, we chose ion-exchange resins as supports and
bond-forming reactions in organic synthesis.1 Organocatalytic synthesized a resin-immobilized organocatalyst 1 (Scheme 1),
asymmetric Michael addition has attracted intensive attention whose structure was similar to the catalyst reported by Sanz-
in recent years due to its environmental friendliness and the hong Luo in 2008. It was employed to catalyze the Michael
generation of multiple stereogenic centers in a single step.2 reaction of cyclohexanone with trans-b-nitrostyrolene (molar
Pyrrolidine-based derivatives have been demonstrated to be ratio 10 : 1) smoothly at room temperature in high yield (95%),
effective asymmetric catalysts for the asymmetric Michael good diastereoselectivity (97 : 3 dr) and enantioselectivity (90%
additions of aldehydes and ketones with nitroolens.3 Number ee) without any solvent or additive.
of highly stereoselective catalysts have been developed and
applied for these reactions.3
The catalytic mechanism of catalyst 1 is similar to many
other proline derivative catalysts which have been reported.7 A
Normally, organocatalysts are difficult to be separated and possible transition state model is proposed as Fig. 2. The
recycled. Environmental concerns associated with chemical secondary amine of the pyrrolidine ring activates the cyclohex-
processes have encouraged the development of environmental anone through the formation of an enamine intermediate. The
friendly methodologies for organic reactions. Recently, immo- hydrogen bond donor between the nitro group and the tertiary
bilization of chiral organocatalysts on supports has received amine, directs the nitrostyrene to attack the re-face of the
more and more interests,4 just because immobilized catalysts enamine.
are easier to be recycled. However, most of them suffered from
low efficiency, poor stereoselectivity and short lifespan.
In 2008, Sanzhong Luo et al. designed and synthesized a CH2Cl2 (10 mL Â 3) and dried at 40 C for 1 h. Unfortunately,
series of noncovalently supported chiral amine catalysts for when catalyst 1 was recycled for 2nd and 3rd runs, its activity
asymmetric direct aldol and Michael addition reactions.5 In this declined dramatically (Table 1).
Aer completion of the reaction, catalyst 1 was simply
separated from the reaction mixture by ltration, washed by
ꢀ
report, the organocatalysts were immobilized on the acidic
In order to gure out the way by which catalyst 1 deactivated
supporter by electrostatic force. Then, in 2011, a comprehensive so quickly, we concentrated the ltrate aer the ltration of
review of non-covalent immobilization of asymmetric organo- catalyst 1. As a result, compound 7 was detected by TLC (thin-
1
catalysts was provided by Long Zhang.6 This strategy inspired us layer chromatography) and was determined by H NMR. This
greatly.
result illustrated that catalyst 1 was unstable, its active
component: compound 7, partly leaked from the resin and
dissolved in the liquid phase.
aSchool of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
E-mail: lgchen@tju.edu.cn
bCollaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Then, what was the percentage of the loss of effective
ingredients? With the purpose of guring out this problem,
pure and enough compound 6 which was got with the method
Tianjin 300072, China
in Scheme 1, was applied to make up 0.1 mol LÀ1, 0.2 mol LÀ1
,
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra10684a
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Scheme 1 Synthesis of catalyst 1 and its application in the Michael addition.
Fig. 1 The structure of catalyst 3.
Fig. 3 The fitting line L1.
Fig. 2 A possible transition state.
Table 1 Successive trials by using recyclable catalyst 1a
Scheme 2 The adsorption–desorption equilibrium in the reaction
mixture.
Concurrently, we increased the amount of the above Michael
addition reaction by 10 times (cylcohexanone 100 mmol,
nitrostyrene 10 mmol, catalyst 1 containing 1 mmol active
loading). Aer completion of the reaction, the mixture was
ltered, washed by CH2Cl2 (100 mL Â 3), and puried by
column chromatography to afford compound 7. Then, it was
employed to react with plenty of benzyl chloride, puried by
column chromatography to obtain compound 6, and 1 mL
methanol was added. Then, It was tested on HPLC (injected
volume: 10 mL). From the equation of L1 and the peak area of the
sample, the concentration of the sample was calculated effort-
lessly. Thus, there were 20.29% compound 7 leaking from
catalyst 1.
Trial
Time (h)
Yieldb (%)
eec (%)
drd
1
2
3
48
72
96
95
86
63
90
89
89
97 : 3
97 : 3
97 : 3
a
Cylcohexanone (10.0 mmol), nitrostyrene (1.0 mmol), reused
1
(contains 0.10 mmol of active loading), solvent-free, room
temperature. Isolated yields. Determined by HPLC using chiralpak
AS-H column. d Determined by 1H NMR.
b
c
0.3 mol LÀ1 and 0.4 mol LÀ1 methanol solutions. Keeping the
injected volume as 10 mL, the four levels of solutions were tested
on HPLC using Agilent Prep-C18 Scalar PN440910-902 column.
By peak area as X-axis and concentration of solution as Y-axis, a
straight line L1 was tted (Fig. 3).
As we knew, in catalyst 1, the linkage between the organo-
catalyst and the support was electrostatic force, which was
weaker than covalent bond. In the reaction mixture, there was
probably an adsorption–desorption equilibrium (Scheme 2).
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Scheme 3 Synthesis of catalysts 2 and 3.
Table 2 Successive trials by using recyclable catalyst 2a
Table 3 Successive trials by using recyclable catalyst 3a
Yieldb (%)
eec (%)
drd
Trial
Time (h)
Yieldb (%)
eec (%)
drd
Trial
Time (h)
1
2
3
4
5
6
7
8
48
48
48
72
72
72
72
72
72
96
96
96
96
96
96
96
95
95
92
93
93
92
90
89
90
92
92
90
89
90
88
85
90
91
90
90
91
91
90
89
90
90
91
89
89
90
90
90
98 : 2
97 : 3
98 : 2
97 : 3
97 : 3
97 : 3
97 : 3
98 : 2
97 : 3
97 : 3
97 : 3
97 : 3
97 : 3
97 : 3
97 : 3
97 : 3
1
2
3
4
5
48
72
72
96
96
95
95
93
93
88
91
90
90
91
89
97 : 3
98 : 2
97 : 3
97 : 3
97 : 3
a
Cylcohexanone (10.0 mmol), nitrostyrene (1.0 mmol), reused
2
(contains 0.10 mmol of active loading) under solvent-free reaction
b
c
conditions at room temperature. Isolated yields. Determined by
HPLC using chiralpak AS-H column. d Determined by H NMR.
1
9
10
11
12
13
14
15
16
Then, if the number of tertiary nitrogen-atom of the orga-
nocatalyst was increased, the binding sites between the support
and organocatalyst would be increased. In this way, the linkage
would be enhanced, and the equilibrium would move le, so
the service life of catalyst would be prolonged. Therefore, we
additionally designed and synthesized two resin-immobilized
organocatalysts 2 and 3 (Scheme 3).
a
Cylcohexanone (10.0 mmol), nitrostyrene (1.0 mmol), reused
3
(contains 0.10 mmol of active loading) under solvent-free reaction
b
c
conditions at room temperature. Isolated yields. Determined by
HPLC using chiralpak AS-H column. d Determined by H NMR.
1
Then, catalysts 2 and 3 were empolyed to catalyze the
asymmetric Michael addition of cyclohexanone with trans-b-
nitrostyrolene. We were pleased to nd that, under the same
reaction conditions, 2 could be used for 5 runs (Table 2),
meanwhile, 3 exhibited much better catalytic performance and
could be used for 16 consecutive runs without signicant loss of
reaction enantioselectivity (Table 3).
We analyzed the ltrate aer the rst run of catalysts 2 and 3,
just like what we did to catalyst 1. However, we could not nd
the compound 9 or 12 by TLC, perhaps because it was only a
trace of active component leaking from the support.
0.05 mol LÀ1, 0.075 mol LÀ1 and 0.10 mol LÀ1 methanol solu-
tions, and other conditions were same with that of testing
catalyst 1. As a result, there were 5.42% compound 9 leaking
from the support of catalyst 2.
We also attempted to provide the percentage of the loss of
active components of catalyst 3 with the similar method.
However, there was so little compound 12 that we could not
isolate it from the ltrate.
As the above results showed, we could conclude that
increasing the number of tertiary nitrogen-atom of organo-
catalyst indeed enhanced the linkage between resin and orga-
nocatalyst, and thus the stability of the catalyst was effectively
improved.
Then, we studied that how much the loss of effective
ingredients was, by using the “tting line” method (Fig. 4).
Compound
8 ,
was applied to make up 0.025 mol LÀ1
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much better than that of nitroolens with chlorine or bromine
(Table 4, entries 4–8), electron-donating groups (Table 4, entries
2–3) or nitro group at o-position (Table 4, entry 10). However,
cyclopentanone, cycloheptanone, propanal and n-butyralde-
hyde only presented the adducts with moderate diaster-
eoselectivities (Table 4, entries 14–17).
In summary, a series of resin-immobilized pyrrolidine-based
chiral organocatalysts have been developed for asymmetric
Michael additions of cyclohexanone with nitrostyrene. Among
them, catalyst 3 exhibited outstanding performance and pre-
sented products with high yield (95%) and good stereo-
selectivities (90% ee, 98 : 2 dr) at room temperature without any
solvent or additive. Moreover, 3 can be easily isolated and reused
for 16 consecutive runs without signicant loss of reaction
enantioselectivity. It could also be applied for a series of Michael
additions of ketones and aldehydes to nitroolens. These
advantages make 3 a potential catalyst for industrial applications.
Fig. 4 The fitting line L2.
Based on the excellent performance of catalyst 3, we applied
it for a wide range of Michael addition reactions between
ketones and aldehydes to nitroolens, the obtained results were
summarized in Table 4. It was obvious that catalyst 3 displayed
satised results for all the Michael additions of cyclohexanone
with nitroolens. Dihydro-2H-pyran-4(3H)-one also showed to
be an efficient Michael donor with high yield (92%) and good
enantioselectivity (79% ee) (Table 4, entry 11). With the increase
of the length of side chain of the ketone, the enantioselectivity
of the Michael addition process was improved (Table 4, entries
12–13). The nitroolen bearing nitro group at p-position of
benzene ring yielded the adduct in excellent enantioselectivity
(99% ee) and diastereoselectivity (99 : 1 dr) (Table 4, entry 9),
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`
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Entry R1
R2 R3
Ph
Yieldb (%) eec (%) drd
1
–(CH2)4–
95
95
90
85
75
88
80
84
70
73
99
85
79
15
90
50
18
25
32
98 : 2
99 : 1
95 : 5
93 : 7
96 : 4
99 : 1
99 : 1
96 : 4
99 : 1
99 : 1
99 : 1
—
99 : 1
80 : 20
96 : 4
95 : 5
56 : 44
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2CH2OCH2)
Me
4-Me–Ph
4-MeO–Ph 96
4-Cl–Ph
3-Cl–Ph
2-Cl–Ph
95
95
94
`
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`
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2,4-Cl–Ph 94
4-Br–Ph
4-NO2
2-NO2
Ph
95
95
95
92
88
70
61
64
82
83
H
Ph
Et
Me Ph
Ph
Ph
Me Ph
Et Ph
–(CH2)3–
–(CH2)5–
H
H
a
Ketones or aldehydes (10.0 mmol), nitroolens (1.0 mmol), catalyst 3
(contains 0.10 mmol of active loading) under solvent-free reaction
b
c
conditions at room temperature. Isolated yields. Determined by
HPLC using chiralpak AS-H column. d Determined by H NMR.
1
3464 | RSC Adv., 2015, 5, 3461–3464
This journal is © The Royal Society of Chemistry 2015