(S)-2,2,6,6-Tetramethyl-N-(pyrrolidin-2-ylmethyl)piperidin-4-amine as an efficient organocatalyst for asymmetric Michael addition

Article abstract of DOI:10.3184/174751912X13383120111261

new organocatalyst derived from proline has been developed and shown to be an efficient catalyst for asymmetric Michael addition reactions of cyclohexanone to nitroolefins with high diastereo- and enantio -selectivities.

Full text of DOI:10.3184/174751912X13383120111261

4
44 RESEARCH PAPER
AUGUST, 444–446
JOURNAL OF CHEMICAL RESEARCH 2012
(
S)-2,2,6,6-Tetramethyl-N-(pyrrolidin-2-ylmethyl)piperidin-4-amine as an
efficient organocatalyst for asymmetric Michael addition
Xiaohui Cao, Ge Wang, Yingying Wei and Ligong Chen*
School of Chemical Engineering andTechnology, Tianjin University, Tianjin, P. R. China
A new organocatalyst derived from proline has been developed and shown to be an efficient catalyst for asymmetric
Michael addition reactions of cyclohexanone to nitroolefins with high diastereo- and enantio -selectivities. (syn: anti
up to 99:1, ee. up to 93%.).
Keywords: asymmetric catalysis, Michael addition, ketones, proline
Recently organocatalysed asymmetric carbon–carbon bond-
forming reactions have received a great deal of attention. The
product of 5 was formed quickly under these reaction condi-
tions. Other studies have indicated that amines behave as
initiators of polymerisation, Barbas’s group have reported that
the addition of Brønsted acids can promote the formation of
enamines thus inhibit the polymerisation. Several sulfonic and
carboxylic acids were surveyed for their effect on the organo-
catalyst 1 catalysed Michael addition of cyclohexanone 4 to
nitrostyrene 5. As indicated in Table 1, the addition of an acid
efficiently improved the reaction. The highest enantioselectiv-
ity of 90% and high diastereoselectivity of 96:4 were observed
in the presence of 20 mol % TFA for the reaction which was
catalysed by 1 in DMSO (Table 1, entry 12).
1
Michael reaction is generally regarded as one of the most
efficient and effective transformation and studies concerning
this reaction have played an important role in the development
2
of modern synthetic organic chemistry. Particularly, Michael
addition reactions of nitroolefins with aldehydes and ketones
are important methods for the synthesis of synthetically useful
γ-nitrocarbonyl compounds, which serve as versatile building
blocks for the preparation of complex organic targets. The
nitro group in these substances can be readily converted into
a variety of new functionalities including amines, nitrile
3
4
5
oxides, ketones, and carboxylic acids. Barbas and List inde-
pendently reported the first organocatalytic addition of ketones
to trans-β-nitrostyrene with L-proline as the catalyst with good
yields but very low enantioselectivities (0–23% ee). Since the
preliminary studies, many organocatalysts derived from pro-
line have been reported to exhibit high activities and excellent
Under the optimised reaction conditions, the Michael addi-
tion of cyclohexanone to a range of nitro-olefins was exam-
ined. As show in Table 2, cyclohexanone efficiently underwent
Michael reactions with different aryl-substituted nitroolefins
to give Michael adducts 6a–g in high yields with excellent
enantio-(85–91% ee) and diastereoselectivities (syn/anti ratio
up to 99/1). The results in Table 3 also show that the nature of
the substituents on the aryl groups only slightly influences the
yields and enatioselectivities. For nitroolefins with electron-
rich groups (methyl and methoxy), the reaction proceeded
smoothly to afford Michael adducts 6b–c in excellent enantio-
6
–16
enantioselectivities for this reaction . In previous studies,
the sterically bulky property was used as a general strategy
1
7,18
for designing the new catalysts . We report here (S)-2, 2, 6,
-tetramethyl-N-(pyrrolidin-2-ylmethyl) piperidin-4-amine 1,
6
which contains a sterically bulky group, to catalyse the Michael
addition with high diastereoselectivity and enantioselectivity
(
90–93% ee) and diastereoselectivities (syn/anti 99/1) (Table
, entries 2–3). For nitroolefins with electron-deficient groups,
(
Scheme 1).
2
the Michael adducts 6d–g were also obtained in high yields
(77–86%) with excellent enantio- (85–90% ee) and diastereo-
selectivities (syn/anti ratio up to 99/1) (Table 2, entries 4–7).
To account for the stereochemical outcome of the Michael
reaction, a plausible transition-state model is proposed in
Fig. 1. The R group occupies a large space to efficiently shield
the si-face of an enamine double bond, which might be a
possible reason for the high stereochemical outcome.
In conclusion, we have designed and prepared a chiral
diamine 1, which effectively catalysed the Michael addition
of cyclohexanone to nitroolefins in high yields with excellent
diastereo- and enantioselectivity.
Results and discussion
Catalyst 1 was prepared in good yields from N-Cbz-L-prolinol
and the corresponding commercially available 2,2,6,6-tetra-
methylpiperidin-4-amine through the reaction sequence shown
in Scheme 1. Firstly, the model Michael reactions of cyclo-
hexanone with trans-β-nitrostyrene catalysed by organocata-
lyst 1 were examined in various organic solvents and the
observed results were summarised in Table 1. When 1 cata-
lysed the reaction without protonic acid in different solvents,
we could not obtain the Michael product (Table 1 entries 1,
5
and 9), because a quantitative amount of polymerisation
Scheme 1 Preparation of organocatalyst 1.
*
Correspondent. E-mail: lgchen@tju.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 445
Table 1 Model Michael reaction
Synthesis of catalyst 1
A stirred solution of Cbz- protected (S)-prolinol 5.5 g (0.023 mol) in
pyridine 20mL was cooled to 0 °C. Then a solution of TsCl 3.2 g
(
0.028 mol) in CH Cl (20 mL) was added dropwise to the above solu-
2 2
tion. After allowing the reaction temperature to rise to r. t., the reaction
mixture was stirred for 18 h. The mixture was diluted with water
(
50 mL) and then the resulted mixture was extracted with CH Cl2
2
(20 mL×3). The combined organic layer was washed with 1M HCl
solution (25 mL×2) and brine (20 mL×2) then dried over anhydrous
Na SO and concentrated in vacuo to give the Cbz-protected (S)-
Entrya Catalyst Solvent Additive Yield syn/antic ee(syn)
2
4
prolinol tosylate 2. (7.3 g, 99 % yield). Then the tosylate 2 was dissol-
ved in 2,2,6,6-tetramethylpiperidin-4-amine (10 mL). The reaction
mixture was stirred at 50 °C for 24 h. The excess amine was recovered
by vacuum distillation and the residue was chromatographed to give
the intermediate 3. The crude product was dissolved in EtOH (20mL)
and the 0.1 g Pd/C (10%) was added. The reaction mixture was stirred
b
d
/%
/%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
MeOH
–
–
–
–
MeOH PhCOOH 41
92:8
91:9
98:2
–
80
81
79
–
MeOH
MeOH
DMF
pTsOH
TFA
–
53
66
–
at r.t under 1atm H overnight. The Pd/C was filtered and the solution
2
DMF
PhCOOH 63
98:2
99:1
98:2
–
97:3
98:2
96:4
95:5
93:7
86
85
87
–
88
86
90
79
84
was concentrated in vacuo. The residue was purified by flash chroma-
tograhy on silica gel to give the desired product 1.
DMF
pTsOH
TFA
–
62
79
–
DMF
(S)-2,2,6,6-Tetramethyl-N-(pyrrolidin-2-ylmethyl)piperidin-4-amine
rt
1
DMSO
(1): Yellow oil, [α]D = +33.4o (1.0, CHCl ) H NMR (500 MHz,
3
1
0
1
2
3
4
DMSO PhCOOH 76
CDCl ) δ: 0.80–0.87(2H, m), .09(6H, s), 1.16(6H, s), 1.28–1.36 (1H,
3
1
1
1
1
DMSO
DMSO
pTsOH
TFA
TFA
TFA
73
85
79
72
m), 1.69–1.88(7H, m), 2.49–2.53(1H, m), 2.67(1H, dd, J = 4.5H 1z,
1
13
J = 11.5Hz), 2.84–2.91(3H, m), 3.17–3.22(1H, m). C NMR (125
2
CH
2
Cl
2
MHz, CDCl3) δ: 25.97, 28.88, 28.90, 35.26, 35.28, 46.38, 46.41,
Toluene
4
6.70, 50.27, 51.27, 52.17, 58.89. HRMS (ESI) Calcd for [M+H]+:
a
1
0 equiv. of ketone, 20 mol% catalyst and 20 mol% additive.
C H N , m/z 240.2434; found 240.2440.
14
30
3
b
c
Isolated yield.
Determined by chiral HPLC.
Determined by chiral HPLC.
Michael addition; general procedure
d
Cyclohexanone (5 mmol) was added to a solution of the amine cata-
lyst 1 (0.1 mmol), TFA (0.1 mmol) and the nitroalkene (0.5 mmol) in
DMSO (2 mL) and the solution was stirred at room temperature for
Table 2 Michael reactions of ketones to nitroolefins
2
4 h except when noted otherwise. The solution was then concen-
trated at room temperature under reduced pressure and the residue
was purified by flash column chromatography on silica gel. Alterna-
tively, ethyl acetate (10 volumes)was added and the solution was
washed with water, 1N HCl, dried (Na SO ) and concentrated to give
2
4
the crude product which was purified by flash chromatography on
silica gel. Compounds 6a–g reported in Table 2 (entries 1–8) are
known in literature and our spectroscopic data are in agreement with
Entry
Ar
Product
Yield/%
Syn:anti
ee/%
[19]
published data
S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone (6a): H NMR
500 MHz, CDCl3) δ 1.10–1.23 (1H, m), 1.43–1.73 (4H, m), 1.97–
.05 (1H, m), 2.26–2.45 (2H, m), 2.57–2.66 (1H, m), 3.65–3.73 (1H,
m), 4.56 (1H, dd, J 12.5, 9.9 Hz), 4.87 (1H, dd, J = 12.5, 4.5 Hz),
.07–7.28 (5H, m); The enantiomeric excess was determined by chiral
HPLC with a Chiralpack AS-H column at 238nm (hexane:2-propanol
.
1
2
3
4
5
6
7
Ph
6a
6b
6c
6d
6e
6f
81
83
76
81
77
86
81
96:4
98:2
95:5
98:2
94:6
99:1
93:7
90
93
90
85
87
90
89
1
(
4-Me-Ph
4-OMe-Ph
2-Cl-Ph
(
2
4-Cl-Ph
7
2,4-Cl-Ph
2-NO
2
-Ph
6g
−
1
9
0:10), 0.7 mL min ; t = 24.1min (minor), 34.5 min (major).
r
a
1
1
0 equiv. of ketone, 20 mol% catalyst and 20 mol% additive.
(S)-2-((R)-2-Nitro-1-p-tolylethyl)cyclohexanone (6b): H NMR
b
c
Isolated yield.
(
2
2
500 MHz, CDCl ) δ 1.20–1.28 (1H, m), 1.57–1.81 (4H, m), 2.03–
.11 (1H, m), 2.32 (3H, s), 2.36–2.42 (1H, m), 2.46–2.50 (1H, m),
.64–2.70 (1H, m), 3.70–3.75 (1H, m), 4.59–4.63 (1H, m), 4.90–4.94
3
Determined by chiral HPLC.
Determined by chiral HPLC.
d
(
1H, m), 7.04 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.0 Hz). The enan-
tiomeric excess was determined by chiral HPLC with a Chiralpack
AS-H column at 238nm hexane: 2-propanol (90:10), 0.7 mL min ;
tr = 16.7min (minor), 29.6 min (major).
−1
(
S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexanone (6c):
1
H NMR (500 MHz, CDCl ) δ 1.19–1.28 (1H, m), 1.57–1.82 (4H, m),
3
2
(
4
.05–2.11 (1H, m), 2.36–2.42 (1H, m), 2.46–2.50 (1H, m), 2.62–2.68
1H, m), 3.69–3.74 (1H, m), 3.79 (3H, s), 4.57–4.61 (1H, m), 4.90–
.93 (1H, m), 6.84 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.5 Hz).
The enantiomeric excess was determined by chiral HPLC with a
Chiralpack AS-H column at 238nm (hexane: 2-propanol 90:10),
Fig. 1 Proposed transition state.
−
1
0
.7 mL min ; t = 42.2min (minor), 68.6 min (major).
r
1
(
S)-2-((R)-1-(2-Chlorophenyl)-2-nitroethyl)cyclohexanone (6d): H
Experimental
NMR (500 MHz, CDCl ) δ 1.30–1.38 (1H, m), 1.59–1.85 (4H, m),
3
Reagents and solvents were obtained from commercial suppliers. All
reactions were carried out under air and monitored by TLC using
commercial aluminum-backed silica gel plates. The ultrasonic reac-
tions were performed in ultrasonic cleaner (KQ5200DE, 70W) with
frequency of 40 MHz. Melting points were observed on YRT-3 Mel-
ting Point Tester and are uncorrected. NMR spectra were recorded on
Varian Inova-400/500 MHz NMR spectrometer with TMS as an inter-
nal reference. MS were recorded on a LCQ Advanted MAX mass
spectrometer. Silica gel (200–300 mesh) was used for the oxidation
reactions and column chromatography. HPLC analysis was measured
using ChiralPak AS-H column.
2
(
7
.09–2.14 (1H, m), 2.37–2.43 (1H, m), 2.47–2.51 (1H, m), 2.90–2.97
1H, m), 4.27–4.31 (1H, m), 4.87–4.94 (2H, m), 7.20–7.25 (3H, m),
.38–7.39 (1H, m). The enantiomeric excess was determined by chiral
HPLC with a Chiralpack AS-H column at 238nm (hexane:2-propanol
−1
9
0:10), 0.7 mL min ; t = 20.2min (minor), 27.7 min (major).
r
1
(
S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)cyclohexanone (6e): H
NMR (500 MHz, CDCl
) δ 1.19–1.28 (1H, m), 1.57–1.83 (4H, m),
3
2.08–2.13 (1H, m), 2.35–2.42 (1H, m), 2.46–2.51 (1H, m), 2.63–2.68
(1H, m), 3.74–3.79 (1H, m), 4.59–4.63 (1H, m), 4.92–4.96 (1H, m),
7.11–7.14 (2H, m), 7.29–7.32 (2H, m). The enantiomeric excess was

4
46 JOURNAL OF CHEMICAL RESEARCH 2012
determined by chiral HPLC with a Chiralpack AS-H column at
3
4
N. Ono, The nitro group in organic synthesis Wiley-VCH, New York,
2001.
K. Sakthivel, W. Notz, T. Bui, C.F. Barbas III, J. Am. Chem. Soc., 2001,
−1
2
3
38nm (hexane:2-propanol 90:10), 0.7 mL min ; t = 21.1min (minor),
5.1 min (major)
r
1
23, 5260
(
S)-2-((R)-1-(2,4-Dichlorophenyl)-2-nitroethyl)cyclohexanone(6f):
1
5
6
B. List, P. Pojarliev, H.J. Martin, Org. Lett., 2001, 3, 2423.
T. Ishii, S. Fujioka, Y. Sekiguchi and H. Kotsuki, J. Am. Chem. Soc., 2004,
H NMR (500 MHz, CDCl ) δ 1.30–1.38 (1H, m), 1.60–1.86 (4H, m),
3
2
.10–2.15 (1H, m), 2.35–2.42 (1H, m), 2.46–2.51 (1H, m), 2.84–2.92
1
26, 9558.
(
1H, m), 4.11–4.24 (1H, m), 4.86–4.92 (2H, m), 7.17 (1H, d, J = 8.0
7
J.M. Betancort, K. Sakthivel, R. Thayumanavan, F. Tanaka and C.F. Barbas,
III Synthesis, 2004, 1509.
Hz), 7.23 (1H, dd, J = 8.0 Hz, J = 2.0 Hz), 7.41 (1H, d, J = 2.0 Hz).
1
2
The enantiomeric excess was determined by chiral HPLC with a
Chiralpack AS-H column at 238nm (hexane:2-propanol 90:10),
8
9
A. Alexakis and O. Andrey, Org. Lett., 2002, 4, 3611.
A.J.A Cobb, D.A. Longbottom, D.M. Shaw and S.V. Ley, Chem. Commun.,
2004, 1808.
A.J.A. Cobb, D.M. Shaw, D.A. Longbottom, J.B. Gold and S.V. Ley, Org.
Biomol. Chem., 2005, 3, 84.
−1
0
.7 mL min ; t = 16.5min (minor), 25.1 min (major)
r
1
(
S)-2-((R)-2-Nitro-1-(2-nitrophenyl)ethyl)cyclohexanone (6g):
H
1
0
NMR (500 MHz, CDCl ) δ 1.19–1.28 (1H, m), 1.57–1.82 (4H, m),
3
2
(
.05–2.11 (1H, m), 2.36–2.42 (1H, m), 2.46–2.50 (1H, m), 2.62–2.68
1H, m), 3.69–3.74 (1H, m), 3.79 (3H, s), 4.57–4.61 (1H, m), 4.90–
.93 (1H, m), 6.84 (2H, d, J = 8.5 Hz), 7.06 (2H, d, J = 8.5 Hz).
11 J. Wang, H. Li, B. Lou, L. Zu, H. Guo and W. Wang, Chem.-Eur. J., 2006,
12, 4321.
4
12 Vishnumaya and V.K. Singh, Org. Lett., 2007, 9, 1117.
13 D.-Q. Xu, L.-P. Wang, S.-P. Luo, Y.-F. Wang, S. Zhang and Z.-Y. Xu, Eur.
J. Org. Chem., 2008, 1049.
The enantiomeric excess was determined by chiral HPLC with a
Chiralpack AS-H column at 238nm (hexane:2-propanol 93:7), 0.7 mL
−1
14 N. Bukuo, Q.-Y. Zhang, D. Kritanjali and D.H. Allan, Org. Lett., 2009, 11,
min ; t = 37.4min (minor), 78.6 min (major).
r
1
037.
1
5
L. Wang, J. Liu, T. Miao, W. Zhou, P. Li, K. Ren and X. Zhang, Adv. Synth.
Catal., 2010, 352, 1629.
Received 2 April 2012; accepted 27 April 2012
Paper 1201242 doi: 10.3184/174751912X13383120111261
Published online: 8 August 2012
16 X. Cao, G. Wang, R. Zhang, Y. Wei, W. Wang, H. Sun and Chen, L. Org.
Biomol. Chem., 2011, 9, 6487.
1
7
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2
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