Chiral pyrrolidine quaternary derivatives as organocatalysts for asymmetric Michael additions

Article abstract of DOI:10.1007/s11164-011-0480-y

A series of chiral pyrrolidine quaternary derivatives were designed and synthesized. It was found that these derivatives are highly efficient organocatalysts for the asymmetric Michael addition reactions of aldehydes and ketones to nitroolefins with high

Full text of DOI:10.1007/s11164-011-0480-y

Res Chem Intermed (2012) 38:1501–1509
DOI 10.1007/s11164-011-0480-y
Chiral pyrrolidine quaternary derivatives
as organocatalysts for asymmetric Michael additions
•
Huichao Sun Ge Wang Xilong Yan Ligong Chen
•
•
Received: 18 December 2011 / Accepted: 28 December 2011 / Published online: 7 January 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A series of chiral pyrrolidine quaternary derivatives were designed and
synthesized. It was found that these derivatives are highly efficient organocatalysts
for the asymmetric Michael addition reactions of aldehydes and ketones to nitro-
olefins with high yields (up to 96%), high enantioselectivities (up to 99% ee), and
high diastereoselectivities (up to 97:3 dr). Furthermore, catalyst 7a could be recy-
cled without remarkable loss of catalytic activity and stereoselectivity.
Keywords Chiral pyrrolidine quaternary derivatives Á Asymmetric Michael
additions Á Organocatalysts Á Nitrostyrenes
Introduction
In recent years, the asymmetric Michael addition reactions have draw much attention
because it is one of the most important carbon–carbon bond-forming reactions in
organic chemistry [1–6]. The organocatalytic asymmetric Michael addition of ketone
to nitroolefins was first reported by List [7] and Barbas [8], independently. Since then,
there has been a tremendous increase in research activities concerning this area, and
many effective organocatalysts have been widely developed [9–17].
Among the various organocatalysts, proline and its derivatives have been
demonstrated to make up a successful class of organocatalysts in enamine
chemistry. Some of them have been developed for asymmetric Michael reactions
of ketones to nitroolefins with high enantioselectivity and diastereoselectivity.
Unfortunately, these organocatalysts have some drawbacks. One major disadvan-
tage is that they cannot be easily recycled [18].
H. Sun Á G. Wang Á X. Yan (&) Á L. Chen
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
e-mail: yan@tju.edu.cn
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H. Sun et al.
Room temperature ionic liquids (RTILs) can be easily separated from organic
reaction systems [19–22]. As a result, quaternary ammonium groups have been
introduced into chiral catalysts [23–31], in which pyrrolidine-type imidazolium ILs
and pyridinium ILs all provided corresponding products with encouraging results
for the Michael additions of ketones or aldehydes to nitroolefins.
In our previous work, several pyrrolidine-based quaternary alkylammonium ionic
liquids were reported, and the structure of these ionic liquids could be easily adjusted
to obtain better catalytic capability by changing each of the alkyl groups [32].
However, these alkyl groups were all straight-chain alkyl groups. Further research on
the influence of functional groups and branched-chain alkyl groups is needed.
Based on the above considerations, a series of chiral pyrrolidine quaternary deriv-
atives were designed and synthesized, which were used as catalysts in asymmetric
Michael additions of cyclohexanone to nitroalkenes with high enantioselectivities
and diastereoselectivities. 7a was designed to study the impact of the cyano group.
7b and 7c were designed to study the effect of three-membered ring and benzene
ring. Furthermore, they could be easily recycled.
Results and discussion
The synthesis of these chiral pyrrolidine quaternary derivatives is shown in Scheme 1.
They were synthesized from commercially available starting material (S)-(2-hydroxy-
methyl) pyrrolidine 1 in six steps. The synthesis of compounds1–5 was described in our
previous work [32]. These catalysts are immiscible in hexane, Et2O, and EtOAc, but are
soluble in polar solvent, such as MeOH, DMSO, CH3CN, and H2O. The difference of
solubility between EtOAc and H2O allowed them to be easily isolated.
The reaction of cyclohexanone and trans-nitrostyrene was explored as a model
reaction. Initially, these chiral ionic liquids were used as catalysts in this reaction.
OMs
OH
OH
PhCH2OCOCl,Et3N
CH3SO2Cl,Et3N
LiBr
N
N
CH2Cl2,0oC to r.t.,83%
CH2Cl2,0oC to r.t.,99%
N
THF,67oC,81%
Cbz
H
Cbz
1
3
2
R
N
Br
N
Me2NH
Pd-C,H2
RBr
Br-
N
N
N
CH3OH/H2O,55oC,86%
EtOH, r.t.
CH3CN,85oC
Cbz
Cbz
4
Cbz
6
5
R
CN
6b,7b:RBr=Br
N
6a,7a:RBr= Br
Br-
N
H
Br
6c,7c:RBr=
7
Scheme 1 Synthesis of chiral pyrrolidine quaternary derivatives
123

Chiral pyrrolidine quaternary derivatives for asymmetric Michael additions
1503
Table 1 The asymmetric Michael additions of cyclohexanone to trans-nitrostyrene over different cat-
alysts
O
O
15 mol % catalyst/
5 mol % TFA
NO2
NO2
+
neat r.t
9a
Entry
Cat.
Cyclohexanone (eq)
Time (h)
Yielda (%)
drb (syn/anti)
eec (syn)
1
7a
7b
7c
7a
7a
20
20
20
20
20
96
96
96
94
93
83
71
97:3
96:4
96:4
97:3
96:4
99
94
97
99
98
2
3
96
4d
5e
a
120
216
Isolated yield
b
c
d
e
Determined by HPLC using Chiralpak As-H column
Determined by HPLC using Chiralpak As-H column
Second cycle of catalyst 7a
Third cycle of catalyst 7a
As shown in Table 1, all the catalysts exhibited good catalytic performance to yield
the corresponding products in good to excellent yields. As 7a showed the best
catalytic activity among the ILs, it was selected as the organocatalyst for the
following studies. The recyclability of 7a was studied, and the results showed that
7a could be easily recovered from the reaction mixture only by filtration after ethyl
ether was added to the reaction mixture. And the Michael addition in the presence of
the recovered 7a yielded similar results but required longer reaction time (entries
4–5). Perhaps the descended purity and the loss of the catalyst 7a in the recycling
process reduced the catalytic activity of the recycled 7a.
Then, 7a was used as the catalyst of the asymmetric Michael reactions in
different solvents and with different acids. As shown in Table 2, the substantial
changes of acids had significant impact on the yield and stereoselectivity. Better
enantioselectivity was obtained in the presence of TFA or CH3COOH rather than
CH3SO3H and p-TsOH (entries 7–9). What is more, when TFA was used as an
additive in the asymmetric Michael reaction, the yield and stereoselectivity were
better than when no acid was used (entry 10, Table 2). Therefore, TFA afforded the
best yield and stereoselectivity among those acids. The reason why acidic additives
had a significant impact may be explained as follows. A proper acidity was helpful
to form the enamine. The acidity of TFA was stronger than CH3COOH but weaker
than CH3SO3H and p-TsOH. So, when TFA was used as an acidic additive, the
reaction system could attain more appropriate acidity than CH3SO3H and p-TsOH,
and without acidic additive. So, TFA was selected as the acidic additive for the
following studies.
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H. Sun et al.
Table 2 The influence of solvents and acids to the reaction of cyclohexanone and trans-nitrostyrene
O
O
NO2
15 mol % 7a
NO2
+
solvents r.t
Entrya
Solvent
Acid (eq)
Time (h)
Yieldb (%)
drc (syn/anti)
eed (%)(syn)
1
2
3
4
5
6
7
8
9
10
a
MeOH
DMF
DMSO
EA
TFA/0.1
144
144
120
168
168
168
216
240
96
77
81
66
72
73
75
43
49
53
79
94:6
97:2
99:1
94:6
91:9
89:11
96:4
95:5
94:6
95:5
93
96
99
89
88
89
77
73
91
89
TFA/0.1
TFA/0.1
TFA/0.1
THF
TFA/0.1
CH2Cl2
Neat
TFA/0.1
CH3SO3H/0.1
p-TsOH/0.1
CH3CO2H/0.1
NO
Neat
Neat
Neat
216
20 equiv of ketone
b
c
d
Isolated yield
Determined by HPLC using Chiralpak As-H column
Determined by HPLC using Chiralpak As-H column
As shown in Table 2, the effects of solvents on the asymmetric Michael reaction
were significant. The reactions in different solvents showed different stereoselec-
tivity and different yields (entries 1–6). In polar solvents, such as MeOH, DMSO,
and DMF, the reaction demonstrated higher stereoselectivity than in EtOAc, THF,
and CH2Cl2. The reason was that the catalysts could be better dissolved in MeOH,
DMSO, and DMF than in EtOAc, THF, and CH2Cl2.
Based on the above work, a variety of other ketones and nitroolefins with
different substituents were investigated to establish a general scope of this
asymmetric transformation. The results are summarized in Table 3. It was found
that nitroolefins with either electron-rich or electron-deficient substituents on the
benzene ring reacted smoothly with cyclohexanone to give the Michael adducts
(entries 1–6), but the reaction yields, stereoselectivity, and enantioselectivities were
different. The differences were caused by the electron cloud density of the benzyl
position of substituted nitroolefins and the space hindrance. The electron-
withdrawing group on the benzene ring of nitroolefin decreased the electron cloud
density of the benzyl position, which was beneficial to the Michael reaction. So 9d
and 9f were obtained in higher yield and stereoselectivity than 9c and 9g (entries 2,
3, 5, and 6). The large substituent group of nitroolefin hindered the nitroolefin to
approach the enamine structure. So 9b and 9e were obtained in low reaction yield
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Chiral pyrrolidine quaternary derivatives for asymmetric Michael additions
1505
Table 3 The asymmetric Michael addition of ketones and aldehydes to trans-nitrostyrenes catalyzed
by 7a
Entrya
Product
Time (h)
96
Yieldb (%)
drc (syn/anti)
eed (%)(syn)
1
57
94:6
96
C6H4-2-NO2
NO2
O
9b
2
3
4
5
6
168
120
120
120
96
71
81
67
82
75
95:5
95:5
96:4
96:4
97:3
94
97
99
98
95
C6H4-4-OMe
O
NO2
9c
C6H4-4-Cl
NO2
O
9d
C6H3-2,4-Cl2
NO2
O
9e
C6H4-2-Cl
NO2
O
9f
C6H4-4-Me
NO2
O
9g
7
8
144
96
–
–
–
C6H5
NO2
9h
O
82
95:5
97
C6H5
NO2
O
9i
123

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H. Sun et al.
Table 3 continued
Entrya
Product
Time (h)
120
Yieldb (%)
61
drc (syn/anti)
93:7
eed (%)(syn)
94
9
C6H5
O
NO2
NO2
9j
O
O
10
120
67
94:6
94
C6H5
9k
S
a
20 equiv of ketone
Isolated yield
b
c
d
Determined by HPLC using Chiralpak As-H column
Determined by HPLC using Chiralpak As-H column
(entries 1 and 4). Moreover, the results indicated that butyraldehyde, tetrahydro-4H-
pyran-4-one, and tetrahydrothiopyran-4-one were also suitable Michael donors
(entries 8–10). However, the reactivity of acetone is lower than cyclohexanone and
butyraldehyde, so it is not a suitable Michael donor for our catalysts. Therefore, the
reaction of acetone to trans-nitrostyrene did not obtain the expected products, and
by-products were not isolated and identified (entry 7).
Conclusions
In conclusion, a new series of chiral pyrrolidine-type quaternary alkyl ammonium
ILs were synthesized, which can be used as efficient catalysts for the asymmetric
Michael reactions of aldehydes and ketones to nitroolefins. These chiral ILs
catalysts can easily be synthesized. All these chiral ILs catalysts are environmen-
tally friendly, and can easily be recovered and reused to provide desired Michael
adducts with high diastereoselectivities and enantioselectivities. Further investiga-
tion on the applications of these new ILs to other asymmetric reactions and the
structure–activity relationship of catalysts are presently being carried out in our
laboratory.
Experimental
General information
Unless specified, Commercial solvents and reagents were used without further
purification.
123

Chiral pyrrolidine quaternary derivatives for asymmetric Michael additions
1507
Analytical thin layer chromatography (TLC) was used for monitoring the
reactions. Column chromatography was performed with silica gel (200–300 mesh).
1H and 13C NMR were recorded by Varian Inova 500 MHz. Mass spectra were
recorded using electrospray ionization (ESI) on LCQ Advanced MAX Mass
instruments. HPLC analysis was measured using ChiralPak AS-H column at
254 nm.
General procedure for the preparation of compounds 6a–6c
Compound 5 (2.6 g, 10.0 mmol), corresponding alkyl bromide (30 mmol) and
CH3CN (40 mL) were added to a 100-mL single neck bottle. After being dissolved,
the reaction mixture was stirred under refluxing and monitored by analytical thin
layer chromatography (PE:EA = 1:1). After removal of CH3CN under vacuum, the
mixture was diluted with 20 mL EtOAc, and then the resulting mixture was
extracted with water (20 mL 93). The combined water layer was concentrated
under vacuum. The resulting residue was purified by silica gel chromatography
(CH3OH:CH2Cl2 = 1:20) to get the corresponding compound 6.
(S)-N-((1-(benzyloxycarbonyl)pyrrolidin-2-yl)methyl)-4-cyano-N,N-dimethylbutan-
1-aminium bromide (6a)
1
Colorless oil. Yield: 58%; HNMR (500 MHz, CDCl3): d = 1.54–1.73 (8H,m),
1.86–1.88 (2H,m), 3.24–3.40 (12H,m), 3.96–3.99 (2H,m), 5.06–5.08 (2H,m),
7.38–7.47 (5H,m).
(S)-1-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)-N-(cyclopropylmethyl)-
N,N-dimethylmethanaminium bromide (6b)
1
Colorless oil. Yield: 69%; HNMR (500 MHz, CD3OD): d = 0.29–0.32 (1H,m),
0.45–0.47 (2H,m), 0.69–0.70 (1H,m), 0.81–0.83 (1H,m), 1.91–2.00 (4H,m), 2.95–3.10
(3H,m), 3.20–3.30 (5H,m), 3.33–3.50 (5H,m), 5.14–5.19 (2H,m), 7.31–7.45 (5H,m).
(S)-N-((1-(benzyloxycarbonyl)pyrrolidin-2-yl)methyl)-N,N-dimethyl-2-
phenylethanaminium bromide (6c)
1
Colorless oil. Yield: 53%; HNMR (500 MHz, CDCl3): d = 1.67–1.73 (3H,m),
1.96–2.00 (1H,s), 3.10–3.16 (3H,m), 3.45–3.50 (8H,m), 3.74–3.76 (1H,m), 3.76–3.84
(1H,s), 3.84–3.95 (1H,s), 4.21–4.29 (1H,s), 5.07–5.15 (2H,m), 7.31–7.37 (10H,m).
General procedure for the preparation of compounds 7a–7c
Ten percent Pd/C was added to the solution of the corresponding compound 6 in
EtOH. The reaction mixture was stirred for 24 h at ambient temperature under
1 atm H2. After filtrating the Pd/C, the solution was concentrated under vacuum to
give the product. The corresponding catalyst 7 was obtained.
123

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H. Sun et al.
(S)-4-cyano-N,N-dimethyl-N-(pyrrolidin-2-yl methyl)butan-1-aminium bromide (7a)
Colorless oil. Yield: 98%; 1HNMR (500 MHz, CDCl3): d = 1.22–1.25 (2H,m),
1.37–1.41 (1H,m), 1.63–1.69 (1H,m), 1.81–1.85 (7H,m), 2.42–2.87 (2H,m), 3.03–3.08
(1H,m), 3.37–3.52 (6H,s), 3.69–3.89 (1H,m), 3.90–3.97 (2H,m); 13CNMR (125 MHz,
CD3OD): d = 119.53, 67.95, 64.14, 57.15, 53.35, 46.76, 31.35, 25.16, 22.31, 17.25,
15.89; MS (ESI) m/z: calcd. for C12H24N3 210.34 (positive ion), found 210.2 (positive
ion).
(S)-1-cyclopropyl-N,N-dimethyl-N-(pyrrolidin-2-ylmethyl)methanaminium
bromide (7b)
Colorless oil. Yield: 85%; 1HNMR (500 MHz, CDCl3): d = 0.58–0.63 (2H,m),
0.80–0.85 (2H,m), 1.07–1.12 (1H,m), 1.38–1.45 (1H,m), 1.65–1.72 (1H,m), 1.79–1.85
(1H,m), 2.08–2.15 (1H,m), 2.87–2.92 (1H,m), 3.02–3.07 (1H,m), 3.44–3.57 (6H,s),
3.59–3.60 (1H,m), 3.62–3.67 (3H,m), 3.85–3.90 (1H,m); 13CNMR (125 MHz,
CD3OD): d = 70.11, 68.37, 53.38, 50.52, 46.74, 31.01, 25.06, 4.51, 4.01; MS (ESI)
m/z: calcd. for C11H23N2 183.31 (positive ion), found 183.1 (positive ion).
(S)-N,N-dimethyl-2-phenyl-N-(pyrrolidin-2-ylmethyl)ethanaminium bromide (7c)
1
Colorless oil. Yield: 99%; HNMR (500 MHz, CDCl3): d = 1.67–1.73 (3H,m),
1.96–2.00 (1H,s), 3.11–3.15 (3H,m), 3.45–3.51 (8H,m), 3.73–3.75 (1H,m), 3.77–3.83
(1H,s), 3.85–3.97 (1H,s), 4.21–4.29 (1H,s), 5.07–5.15 (2H,m); 13CNMR (500 MHz,
CD3OD): d = 136.01, 129.07, 128.81, 127.16, 67.87, 66.07, 53.46, 50.97, 46.77,
31.35, 28.85, 25.17; MS (ESI) m/z: calcd. for C15H25N2 233.37 (positive ion), found
233.1 (positive ion).
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