Asymmetric Michael additions catalysed by functionalised quaternary alkylammonium ionic liquids

Article abstract of DOI:10.3184/174751912X13280326501363

Some functionalised quaternary alkylammonium ionic liquids were synthesised and examined as organocatalysts for asymmetric Michael additions of aldehydes and ketones to nitroolefins. All of them exhibited excellent enantioselectivities (>99% ee) and diast

Full text of DOI:10.3184/174751912X13280326501363

96 RESEARCH PAPER
FEBRUARY, 96–99
JOURNAL OF CHEMICAL RESEARCH 2012
Asymmetric Michael additions catalysed by functionalised quaternary
alkylammonium ionic liquids
Ge Wanga,b, Huichao Suna, Xiaohui Caoa, Yang Lia and Ligong Chena*
aSchool of Chemical Engineering andTechnology, Tianjin University, Tianjin, 300072, P. R. China
bNational Pesticide Engineering Research Center (Tianjin), Nankai University, Tianjin 300071, P. R. China
Some functionalised quaternary alkylammonium ionic liquids were synthesised and examined as organocatalysts
for asymmetric Michael additions of aldehydes and ketones to nitroolefins. All of them exhibited excellent enantiose-
lectivities (>99% ee) and diastereoselectivities (> 99/1 d/r). One of the catalysts (S)-N,N-dimethyl-N-pyrrolidin-2-
ylmethyl)-2-methylpropan-1-aminium bromide could be recovered for reuse with similar results, and triethylamine
was found to be an effective additive to enhance its catalytic activity.
Keywords: asymmetric Michael additions, quaternary alkylammonium ionic liquids, catalysis
Recently, room temperature ionic liquids (RTILs) have been
widely studied.1–2 Due to their particular properties, ILs
can easily be separated from reaction systems.3 So they have
been widely used as solvents or catalysts for various organic
reactions.4 Furthermore, it is of considerable interest to obtain
functionalised ILs by modifying normal ILs.5–10
Indeed, many groups have introduced chiral pyrrolidine
groups into ILs to obtain chiral ILs which can effectively
catalyse asymmetric Michael additions of cyclohexanone to
nitroalkenes.11–22 Encouraging results were seen with some
pyrrolidine-type imidazolium ionic liquids, DABCO ionic
liquids and pyridinium ionic liquids. But all of those ILs
can only be recovered and reused for only a few times. So it
would be useful to increase the catalytic activity of recycled
catalyst.
We previously reported several chiral pyrrolidine-based
quaternary alkylammonium ILs which catalysed asymmetric
Michael additions of cyclohexanone to nitroalkenes in moder-
ate yields with excellent stereoselectivity23 (Scheme 1).
In order to obtain better stereoselectivity and yield of asym-
metric Michael additions and to study the structure-activity
relationship of catalysts, we designed and synthesised three
novel chiral pyrrolidine-based quaternary alkylammonium ILs
(Scheme 2). All of them were used as organocatalysts in the
asymmetricMichaeladditionsofcyclohexanonetonitroalkenes
and the results are reported here.
quaternary alkylammonium ionic liquids 8a–c were prepared
and their catalytic properties evaluated in the Michael addition
of cyclohexanone to trans-nitrostyrene. Representative results
are summarised in Table 1.
Firstly, when compound 8a was used as a catalyst, excellent
enantioselectivity and diastereoselectivity were obtained but
yields were only moderate. Also it required much longer reac-
tion time (552 h) than compound 1a (144 h).23 A plausible
reason is the isopropyl group of 8a could hinder the approach
of trans-nitrostyrene to the enamine in the transition state due
to its large steric effect, as shown in Scheme 3. In contrast,
compound 8b showed excellent enantioselectivity, diastere-
oselectivity and yield of Michael addition with a similar
reaction time (144 h) to compound 1a. The reason may be that
the branched methyl group of 8b is at the β-position of the
quaternary ammonium N atom which would not hinder the
approach of trans-nitrostyrene to the enamine in the transition
state like 8a. Compound 8c showed similar catalytic property
to 8b. But when no TFA was added, the reaction time was
prolonged and the reaction yield decreased. This result
indicated that the hydroxyl group of compound 8c could not
replace the acidic additive.
Then the recyclability of the catalyst 8b was examined in
the Michael addition of cyclohexanone to trans-nitrostyrene
(Table 2). The catalyst 8b could be easily recovered from
the reaction mixture by addition of water. The aqueous
phase was washed three times with EA, concentrated in vacuo,
from which 8b was obtained. When recovered 8b was used
to catalyse Michael addition of cyclohexanone to trans-
nitrostyrene, similar results were obtained but with a prolonged
reaction time. Interestingly, triethylamine was found to be an
effective additive to enhance the catalytic activity of recovered
8b. When triethylamine was added to the reaction mixture,
the reaction was complete in much shorter time. In the
same reaction time, the reaction with triethylamine exhibited
much higher conversion of trans-nitrostyrene than the reaction
without triethylamine.
Results and discussion
In order to improve the stereoselectivity and yield of asym-
metric Michael additions, three new pyrrolidine-based chiral
Encouraged by the results described above, the effects of
acidic additives and solvents to the reaction were investigated,
and the results are shown in Table 3. It was reported that acidic
additives exhibited important impact on the yield and enanti-
oselectivity of the reaction catalysed by compound 1c.23 But
when 8b was used as a catalyst of the Michael reaction, a
similar stereoselectivity to TFA was obtained in the presence
of AcOH, CH3SO3H and p-TsOH (entries 7–9). Also the
reaction yield in the presence of CH3SO3H was lower than that
of TFA, AcOH and p-TsOHFinally, it was found that the
Michael reaction could proceed without acidic additive to
afford similar results (Entry 10). The effect of solvents on the
model reaction catalysed by 8b was not as significant as
that on 1c. The stereoselectivity and reaction times in different
solvents were similar, but yields varied (entries 1–6).
Scheme 1 The Michael reaction catalysed by chiral
quaternary alkylammonium ILs reported by Wang et al.23
* Correspondent. E-mail: lgchen@tju.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 97
Scheme 2 Synthesis of chiral quaternary alkylammonium ILs.
Table
1
Michael additions of cyclohexanone to trans-
Table 2 Recycling studies of 8b catalysed Michael addition of
cyclohexanone to trans-nitrostyrene with or without
triethylamine
nitrostyrene
Entry
Cat.
Time
/h
Yield a
/%
syn
ee
/antib
(syn)/%b
Entry
Time
/h
11a/9aa
Yieldb
/%
syn
ee
/antic (syn)/%c
1
2
3
4
8a
8b
8c
552
144
168
336
68
92
89
64
96/4
98/2
97/3
99/1
97
96
99
99
1d
2e
130
130
178
178
240
202
16
1: 6
1: 19
1: 23
1: 41
–
–
–
–
–
96/4
96/4
96/4
96/4
96/4
96/4
97/3
96/3
97/3
95/5
96/4
95/5
96/4
95/5
95/5
95/5
96/4
96
94
95
95
95
95
98
96
96
96
96
95
96
97
97
97
97
8cc
3d
4e
a Isolated yield.
5d
70
79
–
b Determined by chiral HPLC.
c No acid added.
6e
–
7f
9: 1
3: 1
2: 1
1: 1
1: 1
1: 10
1: 3
1: 14
–
8g
16
–
9f
64
–
10g
11f
12g
13f
14g
15f
16g
17h
64
–
184
184
256
256
760
280
480
–
–
–
–
68
70
68
–
–
a The reaction mixture determined by chiral HPLC.
b Isolated yield.
Scheme 3 Plausible transition state.
c Determined by chiral HPLC.
d Second cycle of catalyst 8b.
e Second cycle of catalyst 8b with 3 mol% triethylamine.
f Third cycle of catalyst 8b.
Next, IL 8b was used as a catalyst for several Michael
reactions of a variety of aldehydes, ketones and nitroolefins.
As shown in Table 4, different substituents on nitroolefins
gave different catalytic results. When a 4-CH3O substituted
nitroolefin was used as a Michael receptor, the Michael
reaction required a much longer reaction time and showed
lower enantioselectivies (entry 2). A conceivable reason is
that as a strong electron-rich group CH3O would increase the
electron cloud density at the benzyl position, which would be
disadvantageous to the Michael reaction. A 2-NO2 substituted
g Third cycle of catalyst 8b with 6 mol% triethylamine.
h Fourth cycle of catalyst 8b with 12 mol% triethylamine.
nitroolefin needed the shortest reaction time, but gave a lower
yield (entry 1). The reason may be that NO2 as an electron-
deficient group would decrease the electron cloud density
at the benzyl position, but the bulk structure of o-NO2 would
hinder the nitroolefin approach to the enamine structure. Other

98 JOURNAL OF CHEMICAL RESEARCH 2012
1
Table 3 The effects of acidic additives and solvents
purchased from Qingdao Haiyang Chemistry Company. H and 13C
NMR were recorded on Varian-500 instruments. Chemical shifts
were reported in ppm down field from internal Me4Si. All the multi-
plet patterns could be assigned from first-order splitting patterns.
Mass spectra were recorded using electrospray ionization (ESI) on
LCQ Advanced MAX Mass instruments. Optical rotations were deter-
mined on an Autopol II polarimeter using 1 mL cell with a 1 dm path
length. HPLC-UV analysis was carried out using ChiralPak AS-H
column at λ = 254 nm.
Entrya Solvent
Acids/
/mol%
Time Yield b syn
ee
/antic (syn)/%c
General procedure
/h
/%
Synthesis of the intermediates: Intermediates 3–6 were obtained
following literature procedures.23–25
1
2
MeOH
DMSO
DMF
CH2Cl2
THF
TFA/5
TFA/5
TFA/5
TFA/5
TFA/5
TFA/5
240
192
216
240
240
216
74
78
79
94
95
62
34
91
91
77
93/7
97/3
96/4
95/5
96/4
96/4
96/4
95/5
99/1
97/3
95
95
96
95
95
95
96
95
99
97
Synthesis of the intermediate 7a: Under N2 protection, intermediate
6 (1.3 g, 5.0 mmol) and MeCN (10 mL) was added to an autoclave.26
After 6 had dissolved, 2-bromopropane (2.3 g, 0.019 mol) was added.
The reaction mixture was stirred at 110 ºC until intermediate 6 had
disappeared by analytical TLC (EA: PE = 1:1), and MeCN was
removed in vacuo. The mixture was dissolved in water (10 mL), then
NaOH (0.2 g, 5.0 mmol) was added. After NaOH had dissolved,
the resulting mixture was extracted with EA (10 mL×3). Then the
combined water layers were concentrated in vacuo. The residue
was purified by flash chromatography (MeOH: CH2Cl2 = 1:10) on
3
4
5
6
EA
7
Neat CH3SO3H/5 192
8
Neat
Neat
Neat
p-TsOH/5
AcOH/5
Neat
192
120
172
9
10
a 20 equiv of ketone.
1
b Isolated yield.
silica gel to give 7a as a yellow solid. (0.9 g, 48% yield); H NMR
c Determined by chiral HPLC.
(500 MHz, D2O) δ ppm: 0.96–1.20 (6H, m), 1.75–1.79 (3H, m),
2.00–2.05 (1H, m), 2.52 –2.89 (6H, m), 3.06–3.14 (2H, m), 3.17–3.41
(4H, m), 4.21 (1H, s), 4.92–5.06 (2H, m), 7.26–7.29 (5H, m).
Synthesis of the intermediate 7b: Under N2 protection, intermediate
6 (1.6 g 6.2 mmol) and MeCN (12 mL) were added to a single neck
bottle.23 After 6 had dissolved, 1-bromo-2-methylpropane (3.2 g
0.023 mol) was added. The reaction mixture was stirred under reflux
until intermediate 6 had disappeared by analytical TLC (EA: PE =
1:1), and MeCN was removed in vacuo. The mixture was diluted
with EA (10 mL), then the resulting mixture was extracted with
water (10 mL×3). The combined water layer was washed with EA
(15 mL×3) and concentrated in vacuo. The residue was purified by
flash chromatography (MeOH: CH2Cl2 = 1:10) on silica gel to give 7b
Table
4
Asymmetric Michael addition of ketones and
aldehydes to trans-nitrostyrenes catalysed by 7c
Entrya R1 R2
R3
Time Product Yield syn
ee
1
/h
/%b /antic /%c
as a colourless oil (1.7 g, 70% yield). H NMR (500 MHz, CD3OD)
δ ppm: 0.86–1.11 (6H, m), 1.90–2.29 (5H, m), 2.91 (1H, s), 2.99
(1H, s), 3.02 (1H, s), 3.18 (3H, s), 3.23 (2H, s), 3.41–3.60 (4H, m),
4.28–4.42 (1H, m), 5.15 (2H, s), 7.32–7.46 (5H, m).
1
2
3
4
5
6
7
8
-(CH2)4- 2-NO2-Ph
-(CH2)4- 4-OMe-Ph 288
48
9b
9c
9d
9e
9f
9g
–
68
90
83
88
99
76
–
97:3 96%
96:4 88%
94:6 96%
99:1 99%
99:1 96%
97:3 95%
-(CH2)4- 4-Cl-Ph
-(CH2)4- 2,4-Cl-Ph
-(CH2)4- 2-Cl-Ph
-(CH2)4- 4-Me-Ph
Me
H
72
72
72
96
–
Synthesis of the intermediate 7c: The procedure was similar to that
used for the synthesis of 7b, with 2-bromoethanol (2.9g 0.023mol)
replacing 1-bromo-2-methyl propane. The residue obtained was
purified by flash chromatography (MeOH: CH2Cl2 = 1:7) on silica gel
H
Et
Ph
Ph
–
–
–
–
1
to give 7c as a white solid (1.8 g, 74% yield); H NMR (500 MHz,
–
–
–
CD3OD) δ ppm: 1.91–2.01 (3H, m), 2.17–2.25 (1H, m), 3.00 (1H, s),
3.07 (1H, s), 3.25 (3H, s), 3.28 (3H, s), 3.44–3.52 (4H, m), 3.56–3.65
(2H, m), 3.80–4.00 (2H, m), 4.38–4.43 (1H, m), 5.15 (2H, s),
7.31–7.47 (5H, m).
a 20 equiv. of ketone.
b Isolated yield.
c Determined by chiral HPLC.
Preparation of 8; general procedure
To a solution of the corresponding intermediate 7 (3.9 mmol) in EtOH
(30 mL), Pd/C (wet, 10%, 0.2g) was added.23,27 The reaction mixture
was stirred at r.t. under 1 atm H2 overnight. After filtering off the Pd/C,
the solution was concentrated in vacuo to give the crude product.
Adding EA (5 mL) to the crude product and vibrating by ultrasonic
wave, the product solidified. The solid catalyst 8a was obtained by
filtration; 8b, 8c as oils were was obtained by pouring off the EA.
8a:Yellow solid, yield 99%). IR (KBr) υ = 2963, 2876, 2079, 1669,
1474, 1117, 905 cm−1; H NMR (500 MHz, D2O) δ ppm: 1.23–1.26
(6H, m), 1.28–1.35 (1H, m), 1.58–1.67 (2H, m), 1.97–2.01 (1H, m),
2.70–2.75 (1H, m), 2.77–2.82 (1H, m), 2.90 (3H, s), 2.91 (3H, s),
3.19–3.23 (1H, m), 3.33–3.36 (1H, m), 3.40–3.43 (1H, m), 3.61–3.66
(1H, m). 13C NMR (125 MHz, D2O) δ ppm: 67.0, 66.2, 52.8, 46. 5, 3.6,
24.2, 15.9, 15.9. [α]Dr. t. = +8.4 (c = 1.46, MeOH); HRMS (ESI+) Calcd
for C10H23N2, m/z 171.1861 (positive ion); found 171.1862 (positive
ion
substituents on nitroolefins showed lesser impact on the
Michael reaction for the electronic and steric effect of those
substituents on the nitroolefin were much weaker. Because of
its lower reaction activity, no Michael product was obtained
when acetone was used as the Michael donor. Surprisingly,
1-butyraldehyde did not give the Michael product either.
In summary, a series of chiral pyrrolidine-type quaternary
alkylammonium ILs have been prepared from (S)-(2-hydroxy-
methyl)pyrrolidine in six steps and used to catalyse the
asymmetric Michael addition reactions of cyclohexanone and
nitroolefins. IL 8b could be easily recovered for recycling.
When triethylamine is added, the catalytic activity of recycled
8b was enhanced. Further investigation on the applications of
these ILs to other Michael reactions is being undertaken in our
laboratory.
8b: Yellow oil. yield 84%; IR (KBr) υ = 2971, 2871, 2776, 1631,
1470, 964, 553 cm−1; 1H NMR (500 MHz, CD3OD) δ ppm: 1.00 (3H,
t, J = 7 Hz), 1.38–1.42 (1H, m), 1.68–1.73 (1H, m), 1.78–1.86 (3H,
m), 2.07–2.12 (1H, m), 2.87–2.99 (2H, m), 3.15 (3H, s), 3.16 (3H, s),
3.27–3.40 (4H, m), 3.59–3.64 (1H, m); 13C NMR (125 MHz, CD3OD)
δ ppm: 68.1, 66.8, 53.4, (50.8, 50.8, 50.7, 50.7), 46.7, 31.4, 25.1, 15.9,
Experimental
Commercial reagents were used without purification unless indicated.
Analytical TLC was performed with various mixtures of ethylacetate
(EA) and petroleum ether (PE) on 0.20 mm silica gel plates and silica
gel (200–300 mesh) was used for flash chromatography. Both were
r. t.
9.7. [α]D = +12.8 (c = 0.97, MeOH); HRMS (ESI+) Calcd for:
C11H25N2, m/z 185.2018 (positive ion); found 185.2010 (positive ion).

JOURNAL OF CHEMICAL RESEARCH 2012 99
References
Recycled 8b: Yellow oil. Recycled yield: 92-95%.HRMS (ESI+);
found 185.2005 (positive ion).
1
2
J. Dupont, R.F. de Souza and P.A.Z. Suarez, Chem. Rev., 2002, 102, 3667.
V. Sans, F. Gelat, N. Karbass, M.I. Burguete, E. Garcia-Verdugo and
S.V. Luis, Adv. Synth. Catal., 2010, 352, 3013.
8c: Colorless oil. yield 97%; IR (KBr) υ = 2963, 2925, 2859, 1731,
1
1640, 1553, 1461, 1076, 740 cm−1; H NMR (500 MHz, CD3OD) δ
3
4
5
6
7
8
9
P. Wasserscheid and W. Keim, Angew Chem. Int. Ed., 2000, 39, 3772.
S.T. Handy, Curr. Org. Chem., 2005, 9, 959.
X. Liang and C. Qi, Catal. Commun., 2011, 12, 808.
ppm: 1.38–1.46 (1H, m), 1.67–1.76 (1H, m), 1.80–1.87 (1H, m),
2.09–2.16 (1H, m), 2.88–2.93 (1H, m), 2.96–3.00 (1H, m), 3.25 (3H,
s), 3.26 (3H, s), 3.44–3.55 (2H, m), 3.58–3.65 (2H, m), 3.66–3.72
(1H, m), 4.00–4.03 (2H, m); 13C NMR (125 MHz, CD3OD) δ ppm:
69.2, 69.2, 69.2, 66.3, 66.2, 66.2, 55.8, 53.4, 51.9, 51.9, 51.8, 51.8,
51.8, 51.7, 46.6, 31.4, 25.1.[α]Dr. t. = +12.0 (c = 0.25, MeOH). HRMS
(ESI+) Calcd for: C9H21N2O, m/z 173.1654 (positive ion); found
173.1644 (positive ion).
General experimental procedure for the Michael addition of
cyclohexanone to nitroalkene by chiral catalyst: TFA (2.85 mg
0.025 mmol) was dropped into a solution of the chiral catalyst
(0.075 mmol) in cyclohexanone (1g, 10mmol). 23 After stirring for 1 h,
nitroalkene (0.5 mmol) was added, and the solution was stirred at r.t.
until nitroalkene had disappeared by Analytical TLC (EA: PE = 1:5).
The solution was diluted with water (5 mL), and the resulting mixture
was extracted with EA (2 mL×3). The combined organic layers were
washed with water (3 mL×2) and brine (3 mL×2) then dried over
anhydrous MgSO4 and concentrated in vacuo to give the crude prod-
uct. PE (3 mL) was added to the crude product and the mixture was
vibrated by ultrasonic waves for 1 h. The corresponding product was
obtained by filtration.
J. Yang, Green Chem., 2010, 12, 201.
S. Yamamoto and A. Kamimura, Chem. Lett., 2009, 38, 1016.
J. Akbari and A. Heydari, Tetrahedron Lett., 2009, 50, 4236.
T. Nakashima, T. Sakakibara and T. Kawai, Chem. Lett., 2005, 34, 1410.
10 X. Yang, Z. Fei, D. Zhao, W.H. Ang, Y. and Li, P.J. Dyson, Inorg. Chem.,
2008, 47, 3292.
11 B. Ni, Q. Zhang and A.D. Headley, Green Chem., 2007, 9, 737.
12 B. Ni, Q. Zhang, K. Dhungana and A.D. Headley, Org. Lett., 2009, 11,
1037.
13 P. Li, L. Wang, M. Wang and Y. Zhang, Eur. J. Org. Chem., 2008, 1157.
14 S. Luo, X. Mi, L. Zhang, S. Liu, H. Xu and J.P. Cheng, Angew. Chem. Int.
Ed., 2006, 45, 3093.
15 S. Luo, L. Zhang, X. Mi, Y. Qiao and J.P. Cheng, J. Org. Chem., 2007, 72,
9350.
16 P. Arumugam and P.T. Perumal, Chem. Lett., 2006, 35, 632.
17 D.Q. Xu, S.P. Luo, Y.F. Wang, A.B. Xia, H.D. Yue, L.P. Wang and Z.Y. Xu,
Chem. Comm., 2007, 4393.
18 H. Sun, D.G. Zhang, C.Q. Zhang and C.B. Liu, Chirality, 2010, 22, 813.
19 W.H. Wang, X.B. Wang, K. Kodama, T. Hirose and G.Y. Zhang,
Tetrahedron, 2010, 66, 4970.
20 D.Z. Xu, Y. Liu, S. Shi and Y. Wang, Tetrahedron Asym., 2010, 21, 2530.
21 V.K. Aggarwal, I. Emme, A. Mereu, Chem. Comm., 2002, 1612.
22 K. Akihiro, T. Takeo, Tetrahedron Lett., 1994, 35, 8805.
23 G. Wang, H. Sun, X. Cao and L. Chen, Cata. Lett., 2011, 141, 1324.
24 D.Y. Chi, J.P.O. Neil, C.J. Anderson, M.J. Welch and J.A. Katzenellen-
Bogen, J. Med. Chem., 1994, 37, 928.
The relative configurations of the products (syn and anti) were
determined by comparison of HPLC data with those reported in the
literature.28 The absolute configurations of the product (e.e) were
determined by comparison of HPLC retention times catalysed by the
racemic proline.29
25 G. Wang, X. Cao, H. Sun and L. Chen, Chin. J. Org. Chem., 2011, 6, 908.
26 F. Vidal, J. Org. Chem., 1959, 24, 680.
27 M. Bergmann and L. Zervas, Ber., 1932, 65, 1192.
28 J.M. Betancourt, K. Sakthivel, R. Thayumanavan, F. Tanaka and C.F. III
Barbas, Synthesis, 2004, 1509.
Received 5 January 2012; accepted 13 January 2012
Paper 1201081 doi: 10.3184/174751912X13280326501363
Published online: 23 February 2012
29 B. List, P. Pojarliev and H.J. Martin, Org. Lett., 2001, 3, 2423.

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