Enantioselective Michael Addition of Pyrroles with Nitroalkenes in Aqueous Media Catalyzed by a Water-Soluble Catalyst

Article abstract of DOI:10.1021/acs.joc.8b01141

A new water-soluble catalytic system was developed and used in an enantioselective Michael addition of pyrroles with nitroalkenes in water to afford nitroethylpyrrole derivatives with both excellent yields and ee values.

Full text of DOI:10.1021/acs.joc.8b01141

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Article
Enantioselective Michael Addition of Pyrroles with Nitroalkenes
in Aqueous Media Catalyzed by a Water-soluble Catalyst
Yang Gui, Yanan Li, Jianan Sun, Zhenggen Zha, and Zhiyong Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01141 • Publication Date (Web): 11 Jun 2018
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Enantioselective Michael Addition of Pyrroles with
Nitroalkenes in Aqueous Media Catalyzed by a Water-
soluble Catalyst
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Yang Gui, Yanan Li, Jianan Sun, Zhenggen Zha, Zhiyong Wang*
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Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft
Matter Chemistry & Center for Excellence in Molecular Synthesis of Chinese Academy of
Sciences, Collaborative Innovation Center of Suzhou Nano Science and Technology & School
of Chemistry and Materials Science, University of Science and Technology of China, Hefei,
Anhui, 230026, P. R. China
E-mail: zwang3@ustc.edu.cn
ABSTRACT: A new water-soluble catalytic system were developed and therefor used in an
enantioselective Michael addition of pyrroles with nitroalkenes in water to afford the
nitroethylpyrrole derivatives with both excellent yields and ee values.
INTRODUCTION
Water, as a safe, inexpensive, and environmentally benign reaction medium, has received
considerable attention in organic synthesis.1 Since the first example of organic reactions in aqueous
media was reported by Breslow in 1980,2 there has been increasing investigation of organic
reactions in aqueous media, especially in the reactions under the catalysis of Lewis acids. With the
development of the reaction in water, it is found that the hydrogen bond of the reaction transition
state, the hydrophobic effect of the molecular structure and the solubility of the reactants in water
have different influences on the reactions. Particularly, in many reactions, the use of water as solvent
can enhance the reaction activity and the selectivity,3 improve the workup process4 and the catalyst
recycle.5 With the in-depth research of the reaction in aqueous media, more attention is focused in
the enantioselective synthesis under the catalysis of Lewis acids in water. As far as we known, the
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first enantioselective metal-catalyzed reaction in water was reported as late as in 1998.1b In the past
few years, the stereoselective aldol reactions, as well as the asymmetric ring-opening of epoxides
with various nucleophiles in water were reported.6 At the same time, quite a few carbon nucleophiles
were used as Michael donors to construct the chiral molecules in aqueous media, most of these
asymmetric reactions involved the use of organocatalysts.7 However, the Lewis acid catalyzed
asymmetric Michael addition in water are rare and these reactions afford the chiral molecules with
poor to moderate enantioselectivity,8 perhaps due to the effect of water on the coordination of the
metal with the chiral ligand. As for the asymmetric metal-catalyzed Michael addition reaction in
aqueous media, we only found one publication for the addition of thiols to α, β-unsaturated ketones
in water to afford the β-keto sulphides.9 The weak interactions between chiral ligands, metal ions
and substrates are sensitive to the aqueous environment. Thus, it can be seen that employment of
the aqueous media as the solvent is a formidable challenge in the asymmetric Michael reaction
catalyzed by Lewis acid. A significant development in this aqueous asymmetric Michael addition
needs a new catalytic system, which can maintain high activity, stability, and selectivity in the
aqueous environment. On the other hand, the nitroethylpyrroles can be the precursors of many
functional molecules, which can be used in molecular electronics, photovoltaic devices and
chemical/biological sensing.10 More importantly, these nitroethylpyrroles are the synthetic moieties
for many pharmaceutical molecules, which have antiarrhythmic, antiamnesic, antihypoxic,
psychotropic, and antihypersensitive.11 For example, the nitroethylpyrrole derivatives can be easily
transformed to nicotine analogues, which has the bioactivity as rennin inhibitors.12 Recently,
enantioselective Michael addition of pyrroles with nitroalkenes was realized in organic solvent
(Scheme 1).12a, 13 Our group has been focusing attention on the research of new methodologies to
realize organic reactions in water for a long time,14 especially the aqueous asymmetric reactions.15
To expand the scope and facilitate the process for metal-catalyzed enantioselective Michael addition
in aqueous media, we prepared a novel water-soluble chiral Schiff based-copper catalyst and
therefor used in the addition of pyrrole to nitroalkenes in water. Herein we report an asymmetric
Michael addition, which was carried out in water and catalyzed by Lewis acid to give the desired
nitroethylpyrroles with high yields and excellent ee values.
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Scheme 1. Previous study and this work on enantioselective Michael addition of pyrroles with
nitroalkenes
RESULTS AND DISCUSSION
The protocol to generate this water-soluble catalytic system was designed based on our previous
studies 12a, 16 The introduction of tertiary amines to the Schiff base ligand can favor the formation of
ammonium salts and enhance the water solubility as well as promote the coordination with the
copper salt (CuBr2). To test our hypothesis, ligand L1 was treated with CuBr2 in methanol for 0.5 h
to give a blue solution. When diethyl ether was added to the blue solution, a large amount of blue
precipitated in the solution (Scheme 2, b1), which can be dissolved in water. We think that this
structure of the Cu-complex in (Scheme 2a) is similar to the previous structure,12a that is, a dinuclear
copper complex with a central Cu2O2 four-membered ring. To our delight, using this water-soluble
blue complex as the catalyst, the addition of pyrrole with nitroalkene 3a in water gave an acceptable
result of 64% ee of the desired product. In order to make it easier for the manipulation, we mixed
up the water-insoluble ligand L1 with CuBr2 in water directly, a homogeneous blue solution (pH =
7) formed in 30 minutes and this catalytic system gave the same result of 64% ee, as shown in
Scheme 2b(2).
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Scheme 2. The design of water-soluble chiral Schiff base-copper catalyst
By virtue of this catalytic system, the reaction of pyrrole with nitroalkene 3a was carried out in the
presence of copper salts and Schiff base ligands in water to optimize the reaction conditions. The
experimental results were summarized in Table 1. Initially, various copper salts were examined in
the presence of Ligand L1. It was found that the counter ions of the copper salts had an influence
on the catalytic activity. Cu(OAc)2 gave the worst yield and the ee value while CuCl2, Cu(NO3)2
and Cu(OTf)2 provided good yields and poor ee values (entries 1-4). Gratifyingly, the use of CuBr2
gave the best result with a yield of 88% and the ee value of 64% (entry 5). When L1 was replaced
with ligand L2 under the same conditions, the reaction can afford the desired product with a higher
enantioselectivity of 71% ee, perhaps due to the increase of electronegativity of nitrogen of amino
group in L2 in comparison with that of L1 (entry 6).
Next, in order to make the water-insoluble nitroalkene 3a fully expose in the catalytic system,
different phase transfer catalyst (PTC) was added into the reaction mixture. It was found that the
addition of PTC enhanced the reaction rate largely and the reaction yield a little while had little
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influence on the enantiomeric excess (entry 7). Then, about 9% organic solvent (0.1 mL in 1 mL
water) was added in the reaction, attempting to convert the reaction mixture to the liquid-liquid
phase from the liquid-solid phase. After screening of the organic solvent (entries 8-12), we found
that a small amount of CHCl3 favored the enantioselectivity of Michael adduct with an ee value of
83% (entry 10). When the reaction temperature was reduced to 0 °C and the reaction time was
prolonged to 72 h, moreover, the adduct 4a can be obtained with an excellent enantioselectivity of
91% ee although the reaction yield was sacrificed to a lower yield of 71% (entry 13). Afterwards,
various PTCs were examined in this reaction to harmony the yield and the ee value. It was found
that sodium laurylsulfonate was the best in this reaction, which can enhance the reaction yield to
93% while the excellent enantioselectivity (91% ee) can be maintained (entry 18). As a result, the
optimal reaction conditions were as follows: CuBr2 as the Lewis acid, L2 as the chiral ligand,
sodium laurylsulfonate as the PTC, 1.0 mL H2O containing 0.1 mL CHCl3 as the solvent, and the
reaction being carried out at 0 °C for 72 h.
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Table 1. Optimization of reaction conditionsa
entry
CuX2
CuCl2
ligand
L1
solvent
H2O
H2O
H2O
H2O
H2O
H2O
PTC
yieldb (%) ee c (%)
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2
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6
-
-
-
-
-
-
84
87
56
77
88
90
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31
48
64
71
Cu(OTf)2
Cu(OAc)2
Cu(NO3)2
CuBr2
L1
L1
L1
L1
CuBr2
L2
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CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
H2O
PTC 5
93
83
89
92
75
84
73
83
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87
91
93
83
70
68
74
83
79
80
91
89
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90
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91
89
8
H2O/toluene = 10:1
-
9
H2O/dichloromethane = 10:1
H2O/chloroform = 10:1
H2O/carbon tetrachloride = 10:1
H2O/1,2-dichloroethane = 10:1
H2O/chloroform = 10:1
H2O/chloroform = 10:1
H2O/chloroform = 10:1
H2O/chloroform = 10:1
H2O/chloroform = 10:1
H2O/chloroform = 10:1
H2O/chloroform = 10:1
-
10
11
12
13d
14d
15d
16d
17d
18d
19d
-
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-
-
-
PTC 1
PTC 2
PTC 3
PTC 4
PTC 5
PTC 6
aUnless otherwise noted, all reactions were performed with 2a (0.6 mmol), 3a (0.2 mmol), L (10
b
mol %), CuBr2 (10 mol %) and PTC (10 mol %) in solvent (1.1 mL), 24 h. Isolated yield.
cDetermined by chiral HPLC analysis. The reaction was performed at 0 °C for 72 h. PTC 1 =
d
Tetrabuylammonium bromide. PTC 2 = Tetrabutylammonium iodide. PTC 3 = Sodium dodecyl
sulfate. PTC 4 = Sodium octanesulfonate. PTC 5 = Sodium laurylsulfonate. PTC 6 = Sodium
hexadecane-1-sulphonate.
With the optimal reaction conditions in hand, we examined the scope of the Michael reaction with
a variety of pyrroles and nitroolefins in water. As shown in table 2, various aromatic nitroolefins
can be employed as Michael acceptors for pyrrole to afford the desired adducts with high
enantioselectivities (90 – 96%) regardless of either electron-deficient or electron-rich substituents
on the phenyl ring of nitroolefins. Nevertheless, the electron-withdrawing group, such as fluoro,
chloro, bromo, trifluoromethyl groups on the para-position of R1 favored the reaction a little in
comparison with the electron-donating groups such as methoxy, methyl groups (entries 1-7). On the
other hand, the steric effect had a negative influence on the reaction. For instance, the nitroalkenes
3h and 3i bearing a substituent at ortho-position of the phenyl ring were less reactive under the
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standard conditions to deliver the desired products with poor yields and ee values. The modified
conditions with higher reaction temperature (5 °C ) and longer reaction time (96 h) were
indispensable to carry out these two reactions to give the desired products with both good yields
and enantioselectivities (entries 8-9). Substitution at meta-position of the phenyl group can tolerate
this reaction, affording the desired products with excellent yield and enantioselectivity (entry 10).
The scope of the reaction substrates can be extended to the hetero-aromatic nitroolefins. For
example, the nitroolefins bearing thienyl and furan ring can be employed as the reaction substrates
in this reaction to give the desired products with excellent yields and ee values (entries 11-12).
Moreover, ring-fused, aliphatic nitroolefins were successfully used in the reaction to give the desired
products with both good yields and ee values under the standard conditions or the modified
conditions (entries 13-16). When 3,4-disubstituted pyrrole (ethyl 4-methyl-1H-pyrrole-3-
carboxylate) was used in the reaction, 5-alkylation product can be obtained with excellent
regioselectivity and enantioselectivity (entry 17).
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Table 2. The enantioselective Michael addition of pyrrole with nitroalkenes in watera
entry
1
3
R1
Ph
4
yieldb (%) ee c (%)
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
93
93
95
97
95
88
76
84
83
91
91
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91
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89
90
2
4-FPh
4-ClPh
4-BrPh
4-CF3Ph
4-MePh
4-MeOPh
2-Cl
3
4
5
6
7
3g
3h
3i
4g
4h
4i
8d
9d
2-Br
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3j
3k
3l
3-Cl
4j
4k
4l
90
91
96
85
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91
2-furyl
2-thienyl
12
13d
14
3m 1-napthyl 4m
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3n
3o
2-napthyl
n-Pr
4n
4o
15
16d
17e
3p cyclohexyl 4p
3q 4q
Ph
aUnless otherwise noted, all reactions were performed with 2a (0.6 mmol), 3a (0.2 mmol), CuBr2
b
(10 mol %), L2 (10 mol %), sodium laurylsulfonate (10 mol %), 0 °C for 72 h. Isolated yield.
cDetermined by chiral HPLC analysis. 5 °C for 96 h. Ethyl 4-methyl-1H-pyrrole-3-carboxylate
d
e
was used instead of 2a.
To demonstrate the practicality and effectiveness of this catalytic system for asymmetric Michael
addition in water, a gram-scale reaction was performed using 3d and pyrrole as the substrates under
the standard conditions for 96 h. To our delight, the desired product 4d can be obtained in 84% yield
with an enantioselectivity of 92%.
Scheme 3. Asymmetric Michael Reaction on a Gram Scalea, b, c
aThe reaction was performed with 2a (15 mmol), 3d (5.0 mmol), L2 (5 mol %), CuBr2 (5 mol %),
sodium laurylsulfonate (10 mol %), in water (25 mL) and CHCl3 (2.5 mL) at 0 °C, 96 h. bIsolated
yield. cDetermined by chiral HPLC analysis.
Based on these results and our previous mechanism study,12a the dinuclear dimeric structure is
dissociated into the monomers in situ, which then coordinates the substrates, that is, a hypothetical
bifunctional mode of action in the transition state is proposed (Figure 1). The nitroalkene is activated
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by chelating with a metal center in the catalyst complex, while the NH in pyrrole is served as a
hydrogen bond donating group to direct the pyrrole to attack the nitroalkene on the Re face. In this
way, the enantioselectivity was obtained.
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Figure 1. Proposed bifunctional mode of action in the transition state
In summary, we designed and prepared a series of Schiff based ligands, which were tertiary amines
derived from amino acids. Moreover, these ligands mixed with CuBr2 can afford the water-soluble
ammonium salts in situ, giving new catalytic systems for the Michael addition of pyrroles to
nitroalkenes in water. By virtue of this water-soluble catalytic system, we developed a Lewis acid
catalyzed Michael addition with carbon nucleophiles in water, delivering a series of
nitroethylpyrrole derivatives with excellent yields and enantioselectivities. Besides, a gram scale of
the asymmetric Michael reaction in water could be achieved by using this water-soluble catalyst.
Further studies on this new catalytic system for other reactions are ongoing in our group.
EXPERIMENT SECTION
1
General Information: H NMR and 13C NMR were recorded on a 400MHz Nuclear Magnetic
Resonance Spectrometer (1H NMR: 400MHz, 13C NMR: 100MHz) using TMS as internal reference.
The chemical shifts (δ) and coupling constants (J) were expressed in ppm and Hz, respectively. UV-
Vis Spectrophotometry was carried out on infrared spectrometer. HPLC analysis was carried out on
HPLC with a multiple wavelength detector by commercial chiral columns. Optical rotations were
measured on a Polarimeter. HRMS (ESI) were recorded on a Q-TOF Premier. Commercially
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available compounds were used without further purification. Solvents were purified according to
the standard procedures unless otherwise noted. Nitroalkenes were prepared according to literature
procedures.13
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Preparation for ligand L1
To a round bottom flask was added magnesium strips (0.36 g, 15 mmol), one small crystal of iodine,
and 4-bromo-N, N-dimethylbenzylamine in dry THF (25 mL). The reaction mixture was stirred at
reflux to start the reaction. A solution of 4-bromo-N, N-dimethylbenzylamine (3.20 g, 15 mmol) in
dry THF (5 ml) was added dropwise over 30 min. After addition, the reaction mixture was continued
to stirring at reflux for 2 hours and cooled to room temperature. Then a solution of methyl (tert-
butoxycarbonyl)-L-phenylalaninate (1.40 g, 5 mmol) in dry THF (5 ml) was added dropwise to the
Grignard reagent at room temperature over 30 min. The resulting mixture was further stirred
overnight and was then quenched with saturated aqueous solution of NH4Cl. The product was
extracted with ethyl acetate and the combined organic phase was dried over Na2SO4. The solvent
was evaporated under reduced pressure and the crude product was used for next step without
purification.
The crude product in CH2Cl2 (15 mL) was added 2,2,2-Trifluoroacetic acid (10 mL), then the
reaction mixture was stirred at room temperature for 5h and concentrated under reduced pressure.
To the residue was added aqueous HCl (2 M, 5.0 mL) and the mixture was extracted with ethyl
acetate (3 x 5 mL). The aqueous layer was basified with aqueous buffer solution of NH3 (1
M)/NH4Cl (1 M) and extracted with dichloromethane (3 x 10 mL). The combined organic phases
were dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude
product was purified by column chromatography (CH2Cl2/MeOH/NEt3 = 100:10:1) to give product
(S)-2-amino-1,1-bis(4-((dimethylamino)methyl)phenyl)-3-phenylpropan-1-ol as a colorless oil
(1.73 g, 83% yield). [α]D20 = -45.5 (c =1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.60-7.53 (m,
4 H), 7.31-7.13 (m, 9 H), 4.52 (br, 1H), 4.16-4.12 (m, 1 H), 3.45-3.32 (m, 4 H), 2.65-2.60 (m, 1 H),
2.46-2.30 (m, 1 H), 2.20 (s, 12 H),1.42 (br, 2 H); 13C NMR (100 MHz, CDCl3) δ 145.7, 143.3, 139.7,
137.3, 136.9, 129.2, 129.1, 129.0, 128.7, 126.5, 125.8, 125.4, 78.5, 64.0, 63.9, 58.3, 45.43, 45.40,
36.8; HRMS (ESI) calcd for C27H36N3O+ [M+H]+ 418.2858, found 418.2857.
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To a solution of chiral amino alcohol (2 mmol) in methanol (10 mL) was added salicylaldehyde
derivative (2 mmol). The solution was stirred for 2 h at room temperature then the solvent was
removed under reduced pressure. The residue was purified by silica gel column chromatography
(CH2Cl2/MeOH = 5/1 as eluent) to give the corresponding Schiff base ligand L1 quantitatively as
yellow foam. [α]D 20 = -54.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 13.91 (br, 1 H), 7.64-
7.30 (m, 8 H), 7.20-7.11 (m, 5 H), 7.00-6.94 (m, 3 H), 6.80-6.70 (m, 1 H), 4.35-4.31 (m, 1 H), 3.51-
3.22 (m, 4 H), 3.10-3.01 (m, 2 H), 2.91-2.79 (m, 1 H), 2.24 (s, 6 H), 2.11 (s, 6 H); 13C NMR (100
MHz, CDCl3): δ 165.8, 160.0, 144.0, 142.7, 138.7, 137.7, 137.4, 135.1, 129.9, 129.7, 129.3, 129.2,
128.5, 126.5, 126.0, 125.9, 124.9-122.2 (q, J = 270.0 Hz), 118.8, 118.4-117.5 (q, J = 30.0 Hz), 117.3,
79.6, 78.7, 63.9, 63.7, 45.4, 45.2, 37.2; 19F NMR (376 MHz, CDCl3) δ -62.6; HRMS (M+H)+
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calcd for C35H39F3N3O2 590.2994, found 590.2995.
Preparation for ligand L2
To a round bottom flask was added magnesium strips (0.36 g, 15 mmol), one small crystal of iodine,
and 2-(4-bromophenyl)-N, N-dimethylethan-1-amine in dry THF (25 mL). The reaction mixture was
stirred at reflux to start the reaction. A solution of 2-(4-bromophenyl)-N, N-dimethylethan-1-amine
(3.41 g, 15 mmol) in dry THF (5 ml) was added dropwise over 30 min. After addition, the reaction
mixture was continued to stirring at reflux for 2 hours and cooled to room temperature. Then a
solution of methyl (tert-butoxycarbonyl)-L-phenylalaninate (1.40 g, 5 mmol) in dry THF (5 ml) was
added dropwise to the Grignard reagent at room temperature over 30 min. The resulting mixture
was further stirred overnight and was then quenched with saturated aqueous solution of NH4Cl. The
product was extracted with ethyl acetate and the combined organic phase was dried over Na2SO4.
The solvent was evaporated under reduced pressure and the crude product was purified by silica gel
column chromatography (CH2Cl2/MeOH/NEt3 = 100:10:1) to give tert-butyl (1,1-bis(4-(2-
(dimethylamino)ethyl)phenyl)-1-hydroxy-3-phenylpropan-2-yl)carbamate as a colorless oil (2.37g,
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87% yield). [α]D = -11.5 (c =1.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.48-7.40 (m, 4 H),
7.28-7.04 (m, 9 H), 4.93 (d, J = 9.4 Hz, 1 H),4.72-4.60 (m, 1 H), 4.13 (br, 1 H), 2.90-2.53 (m, 6 H),
2.54-2.40 (m, 4 H), 2.28 (s, 6 H), 2.25 (s, 6 H), 1.20 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 155.9,
143.7, 143.1, 139.2, 138.7, 138.5, 129.3, 128.7, 128.3, 128.2, 126.1, 126.0, 125.6, 115.7, 80.8, 79.3,
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61.4, 61.2, 46.0, 45.4, 45.3, 36.1, 33.7, 33.5, 28.1; HRMS (ESI) calcd for C34H48N3O3 [M+H]+
546.3696, found 546.3694.
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The product in CH2Cl2 (15 mL) was added 2,2,2-Trifluoroacetic acid (10 mL), then the reaction
mixture was stirred at room temperature for 5h and concentrated under reduced pressure. To the
residue was added aqueous HCl (2 M, 5.0 mL) and the mixture was extracted with ethyl acetate (3
x 5 mL). The aqueous layer was basified with aqueous buffer solution of NH3 (1 M)/NH4Cl (1 M)
and extracted with dichloromethane (3 x 10 mL). The combined organic phases were dried over
anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was used for
next step without purification.
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To a solution of chiral amino alcohol (2 mmol) in methanol (10 mL) was added salicylaldehyde
derivative (2 mmol). The solution was stirred for 2 h at room temperature then the solvent was
removed under reduced pressure. The residue was purified by silica gel column chromatography
(CH2Cl2/MeOH = 5/1 as eluent) to give the corresponding Schiff base ligand L2 quantitatively as
yellow foam. [α]D 20 = -76.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.54-7.50 (m, 4 H),
7.40-7.31 (m, 2 H), 7.25-7.00 (m, 8 H), 7.05-6.91 (m, 3 H), 6.81-6.70 (m, 1 H), 4.31 (d, J = 8.9 Hz,
1 H), 3.38 (br, 1 H), 3.08-3.01 (d, J = 13.0 Hz, 1 H), 2.88-2.72 (m, 4 H), 2.71-2.64 (m, 2 H), 2.62-
2.51 (m, 2 H), 2.50-2.41 (m, 2 H), 2.30 (s, 6 H), 2.23 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 165.6,
160.5, 142.9, 141.8, 139.0, 138.9, 138.7, 135.2, 130.0, 129.7, 128.8, 128.6, 128.4, 126.5, 126.3,
126.1, 125.0-122.3 (q, J = 270.9 Hz), 118.8, 118.2-117.9 (q, J = 30.4 Hz), 117.1, 79.4, 78.5, 61.2,
61.1, 45.3, 45.2, 37.3, 33.7, 33.5; 19F NMR (376 MHz, CDCl3) δ -62.6; HRMS (M+H )+ calcd
for C37H43F3N3O2 618.3307, found 618.3307.
General procedures for Michael addition of Pyrroles with Nitroalkenes in Aqueous Media:
A mixture of Ligand L2 (0.02 mmol, 12.4 mg), CuBr2 (0.02 mmol, 4.5 mg) in water (1.0 mL) was
stirred for 1h at ambient atmosphere, nitroalkenes (0.2 mmol), CHCl3 (0.1mL) and sodium
laurylsulfonate (0.02 mmol, 5.4 mg) were then added. The resulting mixture was cooled to 0 °C .
After 30 min, corresponding pyrrole (0.6 mmol) was added slowly by syringe. After reactions were
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finished (monitored by TLC), the organic phase was separated, evaporated in vacuo. Purification by
column chromatograph afforded Michael adducts.
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Experimental data of Michael adducts
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(S)-2-(2-nitro-1-phenylethyl)-1H-pyrrole (4a)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 93% yield. [α]D20 -88.4 (c = 1.0,
CH2Cl2, 91%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0
mL/min, T = 23°C, UV = 254 nm, tR = 9.1 min (major), tR = 10.0 min (minor).1H NMR (400 MHz,
CDCl3): δ 7.84 (br, 1 H), 7.40-7.27 (m, 3 H), 7.25-7.20 (m, 2 H), 6.68 (m, 1 H), 6.16 (dd, J = 6.0
Hz, 3.2 Hz, 1 H), 6.08 (m, 1 H), 4.97 (dd, J = 12.0 Hz, 7.2 Hz, 1 H), 4.89 (t, J = 7.5 Hz, 1 H), 4.80
(dd, J = 12.0 Hz, 7.6Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 138.0, 129.2, 128.9, 128.2, 127.9,
118.2, 108.7, 105.8, 79.2, 42.9;
(S)-2-(1-(4-fluorophenyl)-2-nitroethyl)-1H-pyrrole (4b)
The title compound was prepared according to the general working procedure and purified by
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column chromatography to give the product as a white solid in 93% yield. m.p. 91-92°C; [α]D
-
89.3 (c =1.0, CH2Cl2, 91%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 95: 5, flow
rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 24.0 min (major), tR = 25.6 min (minor). 1H NMR
(400 MHz, CDCl3): δ 7.86 (br, 1 H), 7.26-7.15 (m, 2 H), 7.07-6.90 (m, 2 H), 6.70 (m, 1 H), 6.17
(dd, J = 6.1 Hz, 2.8 Hz, 1 H), 6.07 (m, 1 H), 4.97 (dd, J = 12.2 Hz, 7.1 Hz, 1 H), 4.88 (t, J = 7.7 Hz,
1 H), 4.76 (dd, J = 12.2 Hz, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 163.6, 161.2, 133.8,
129.64, 129.56, 128.7, 118.4, 116.3, 116.1, 108.7, 105.9, 79.2, 42.2; 19F NMR (376 MHz, CDCl3)
δ -113.7;
(S)-2-(1-(4-chlorophenyl)-2-nitroethyl)-1H-pyrrole (4c)
The title compound was prepared according to the general working procedure and purified by
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column chromatography to give the product as a white solid in 95% yield. m.p. 103-104°C; [α]D
-75.9 (c = 1.2, CH2Cl2, 94%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90:10, flow
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rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 11.5 min (minor), tR = 12.3 min (major). 1H NMR
(400 MHz, CDCl3): δ 7.86 (br, 1 H), 7.34-7.29 (m, 2 H), 7.18-7.14 (m, 2 H), 6.70 (m, 1 H), 6.16
(dd, J = 6.1 Hz, 2.8 Hz, 1 H), 6.06 (s, 1 H), 4.96 (dd, J = 12.2 Hz, 7.1 Hz, 1 H), 4.86 (t, J = 7.8 Hz,
1 H), 4.77 (dd, J = 12.2 Hz, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 136.5, 134.1, 129.4, 129.3,
128.3, 118.5, 108.8, 106.0, 79.0, 42.3;
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(S)-2-(1-(4-bromophenyl)-2-nitroethyl)-1H-pyrrole (4d)
The title compound was prepared according to the general working procedure and purified by
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column chromatography to give the product as a white solid in 97% yield. m.p. 94-95°C; [α]D
-
60.4 (c = 1.2, CH2Cl2, 94%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow
rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 12.3 min (minor), tR = 13.8 min (major). 1H NMR
(400 MHz, CDCl3): δ 7.86 (br, 1 H), 7.49-7.45 (m, 2H), 7.12-7.07 (m, 2 H), 6.70 (m, 1 H), 6.16 (dd,
J = 6.1 Hz, 2.8 Hz, 1 H), 6.06 (m, 1 H), 4.96 (dd, J = 12.2 Hz, 7.0 Hz, 1 H), 4.85 (t, J = 7.8 Hz, 1
H), 4.77 (dd, J = 12.2 Hz, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 137.1, 132.4, 129.6, 128.2,
122.2, 118.5, 108.8, 106.0, 78.9, 42.4;
(S)-2-(2-nitro-1-(4-(trifluoromethyl)phenyl)ethyl)-1H-pyrrole (4e)
The title compound was prepared according to the general working procedure and purified by
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column chromatography to give the product as a white solid in 95% yield. m.p. 89-90°C; [α]D
-
58.6 (c = 0.81, CH2Cl2, 96%ee); HPLC: Daicel Chiralpak OJ-H, hexane: 2-propanol = 70: 30, flow
rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 15.9 min (major), tR = 22.1 min (minor). 1H NMR
(400 MHz, CDCl3): δ 7.91 (br, 1 H), 7.62 (d, J = 8.1 Hz, 2 H), 7.37 (d, J = 8.1 H, 2 H), 6.72 (m, 1
H), 6.19 (dd, J = 6.0 Hz, 2.9 Hz, 1 H), 6.10 (m, 1 H), 5.10-4.90 (m, 2 H), 4.88-4.80 (m, 1 H); 13
C
NMR (100 MHz, CDCl3): δ 142.1, 130.9-129.9 (q, J = 32.6 Hz ), 128.4, 127.9, 126.2, 125.2-119.8
(q, J = 270.6 Hz ), 118.7, 108.9, 106.3, 78.8, 42.7; 19F NMR (376 MHz, CDCl3) δ -62.7;
(S)-2-(2-nitro-1-(p-tolyl)ethyl)-1H-pyrrole (4f)
The title compound was prepared according to the general working procedure and purified by
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column chromatography to give the product as a white solid in 88% yield. m.p. 101-102°C; [α]D
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-72.2 (c = 1.4, CH2Cl2, 91%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 95: 5, flow
rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 16.7 min (major), tR = 18.1 min (minor). 1H NMR
(400 MHz, CDCl3): δ 7.81 (br, 1 H), 7.16-7.08 (m, 4 H), 6.66 (m, 1 H), 6.15 (m, 1 H), 6.06 (s, 1 H),
4.95 (dd, J = 11.9 Hz, 7.0 Hz, 1 H), 4.84 (m, 1 H), 4.77 (dd, J = 11.9 Hz, 7.9 Hz, 1 H), 2.32 (s, 3
H); 13C NMR (100 MHz, CDCl3): δ 136.9, 133.8, 128.9, 128.1, 126.8, 117.0, 107.6, 104.6, 78.3,
41.5, 20.0;
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(S)-2-(1-(4-methoxyphenyl)-2-nitroethyl)-1H-pyrrole (4g)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 76% yield. [α]D20 -70.3 (c = 1.0,
CH2Cl2, 90%ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-propanol = 80: 20, flow rate = 0.8
mL/min, T = 23°C, UV = 254 nm, tR = 26.4 min (minor), tR = 34.6 min (major). 1H NMR (400 MHz,
CDCl3): δ 7.84 (br, 1 H), 7.16-7.11 (m, 2 H), 6.89-6.83 (m, 2 H), 6.68 (m, 1 H), 6.15 (m, 1 H), 6.06
(m, 1 H), 4.95 (dd, J = 12.0 Hz, 7.0 Hz, 1 H), 4.84 (m, 1 H), 4.75 (dd, J = 12.0 Hz, 8.1 Hz, 1 H),
3.78 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 159.3, 129.8, 129.3, 129.1, 118.1, 114.6, 108.6, 105.6,
79.4, 55.3, 42.2;
(S)-2-(1-(2-chlorophenyl)-2-nitroethyl)-1H-pyrrole (4h)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 84% yield. [α]D20 -79.7 (c = 0.8,
CH2Cl2, 89%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 0.8
mL/min, T = 23°C, UV = 254 nm, tR = 9.5 min (major), tR = 10.8 min (minor). 1H NMR (400 MHz,
CDCl3): δ 8.01 (br, 1 H), 7.45-7.38 (m, 1 H), 7.27-7.18 (m, 2 H), 7.15-7.09 (m, 1 H), 6.70 (m, 1 H),
6.18-6.12 (m, 2 H), 5.45 (m, 1 H), 4.96-4.83 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ 135.7, 133.6,
130.2, 129.3, 129.0, 127.9, 127.7, 118.4, 108.7, 106.3, 77.2, 39.3;
(S)-2-(1-(2-bromophenyl)-2-nitroethyl)-1H-pyrrole (4i)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 83% yield. [α]D20 -83.5 (c = 1.0,
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CH2Cl2, 90%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 95: 5, flow rate = 0.8
mL/min, T = 23°C, UV = 254 nm, tR = 21.2 min (major), tR = 26.0 min (minor). 1H NMR (400 MHz,
CDCl3): δ 8.01 (br, 1 H), 7.61 (dd, J = 7.9 Hz, 1.2 Hz, 1 H), 7.29-7.24 (m, 1 H), 7.18-7.05 (m, 2 H),
6.71 (m, 1 H), 6.18-6.09 (m, 2 H), 5.45 (m, 1 H), 4.94-4.80 (m, 2 H); 13C NMR (100 MHz, CDCl3):
δ 137.4, 133.6, 129.5, 129.1, 128.3, 127.9, 124.2, 118.4, 108.7, 106.3, 77.3, 41.8;
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(S)-2-(1-(3-chlorophenyl)-2-nitroethyl)-1H-pyrrole (4j)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 90% yield. [α]D20 -88.6 (c = 1.0,
CH2Cl2, 92%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0
mL/min, T = 23°C, UV = 254 nm, tR = 9.0 min (major), tR = 9.9 min (minor). 1H NMR (400 MHz,
CDCl3): δ 7.90 (br, 1 H), 7.30-7.25 (m, 2 H), 7.21 (s, 1 H), 7.15-7.09 (m, 1 H), 6.70 (m, 1 H), 6.17
(dd, J = 6.2 Hz, 2.8 Hz, 1 H), 6.07 (m, 1 H), 4.96 (dd, J = 12.1 Hz, 7.1 Hz, 1 H), 4.86 (m, 1 H), 4.78
(dd, J = 12.1 Hz, 7.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 140.1, 135.1, 130.5, 128.4, 128.12,
128.08, 126.1, 118.6, 108.8, 106.1, 78.9, 42.6;
(S)-2-(1-(furan-2-yl)-2-nitroethyl)-1H-pyrrole (4k)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 91% yield. [α]D20 +16.1 (c = 1.0,
CH2Cl2, 89%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0
mL/min, T = 23°C, UV = 254 nm, tR = 9.5 min (minor), tR = 10.8 min (major). 1H NMR (400 MHz,
CDCl3): δ 8.24 (br, 1 H), 7.40 (m, 1 H), 6.71 (m, 1 H), 6.33 (dd, J = 3.2 Hz, 1.9 Hz, 1 H), 6.20-6.07
(m, 3 H), 5.01 (t, J = 7.7 Hz, 1 H), 4.92-4.78 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ 150.7, 142.8,
126.3, 118.4, 110.7, 108.9, 107.9, 106.7, 77.8, 37.7;
(S)-2-(2-nitro-1-(thiophen-2-yl)ethyl)-1H-pyrrole (4l)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 96% yield. [α]D20 -44.2 (c = 1.0,
CH2Cl2, 92%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0
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mL/min, T = 23°C, UV = 254 nm, tR = 11.0 min (minor), tR = 11.8 min (major). 1H NMR (400 MHz,
CDCl3): δ 8.02 (br, 1 H), 7.25 (dd, J = 4.9 Hz, 1.3 Hz, 1 H), 6.98-6.92 (m, 2 H), 6.70 (m, 1 H), 6.17
(m, 1 H), 6.10 (m, 1 H), 5.20 (m, 1 H), 4.94 (dd, J = 12.9 Hz, 7.5 Hz, 1 H), 4.81 (dd, J = 12.9 Hz,
8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 141.0, 128.3, 127.2, 125.9, 125.6, 118.3, 108.9, 106.0,
79.7, 38.2;
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(S)-2-(1-(naphthalen-1-yl)-2-nitroethyl)-1H-pyrrole (4m)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 85% yield. [α]D20 -50.5 (c = 1.1,
CH2Cl2, 89%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 95: 5, flow rate = 1.0
mL/min, T = 23°C, UV = 254 nm, tR = 19.7 min (minor), tR = 20.8 min (major). 1H NMR (400 MHz,
CDCl3): δ 8.11 (m, 1 H), 7.90-7.69 (m, 3 H), 7.60-7.47 (m, 2 H), 7.41 (m, 1 H), 7.24 (m, 1 H), 6.62
(m, 1 H), 6.21-6.14 (m, 2 H), 5.75 (m, 1 H), 5.04 (dd, J = 13.1 Hz, 9.0 Hz, 1 H), 4.93 (dd, J = 13.2
Hz, 6.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 134.2, 133.6, 131.0, 129.3, 129.0, 128.9, 127.2,
126.2, 125.5, 122.4, 118.3, 108.7, 106.5, 78.5, 38.8;
(S)-2-(1-(naphthalen-2-yl)-2-nitroethyl)-1H-pyrrole (4n)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 94% yield. [α]D20 -62.6 (c = 1.2,
CH2Cl2, 93%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0
mL/min, T = 23°C, UV = 254 nm, tR = 14.1 min (minor), tR = 17.0 min (major). 1H NMR (400 MHz,
CDCl3): δ 7.84-7.70 (m, 4 H), 7.68 (m, 1 H), 7.53-7.45 (m, 2 H), 7.31-7.27 (m, 1 H), 6.66 (m, 1 H),
6.18 (m, 1 H), 6.12 (m, 1 H), 5.08-5.00 (m, 2 H), 4.94-4.85 (m, 1 H); 13C NMR (100 MHz, CDCl3):
δ 135.3, 133.4, 132.9, 129.2, 128.9, 127.9, 127.8, 127.0, 126.7, 126.5, 125.4, 118.4, 108.7, 105.9,
79.1, 43.1;
(S)-2-(1-nitropentan-2-yl)-1H-pyrrole (4o)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a light yellow oil in 92% yield. [α]D20 +30.3 (c = 1.0,
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CH2Cl2, 94%ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-propanol = 98: 2, flow rate = 0.8
mL/min, T = 23°C, UV = 254 nm, tR = 50.7 min (major), tR = 56.9 min (minor). 1H NMR (400 MHz,
CDCl3): δ 8.10 (br, 1 H), 6.69 (m, 1 H), 6.16 (m, 1 H), 6.00 (m, 1 H), 4.51 (m, 2 H), 3.52 (m, 1 H),
1.66 (m, 2 H), 1.32 (m, 2 H), 0.91 (t, J = 7.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 130.0, 117.3,
108.8, 105.4, 80.4, 37.3, 34.5, 20.2, 13.8;
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(S)-2-(1-cyclohexyl-2-nitroethyl)-1H-pyrrole (4p)
The title compound was prepared according to the general working procedure and purified by
20
column chromatography to give the product as a light yellow oil in 87% yield. [α]D +10.3 (c =
0.81, CH2Cl2, 88%ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-propanol = 95: 5, flow rate = 1.0
mL/min, T = 23°C, UV = 254 nm, tR = 23.7 min (major), tR = 26.3 min (minor). 1H NMR (400 MHz,
CDCl3): δ 8.04 (br, 1 H), 6.67 (m, 1 H), 6.15 (m, 1 H), 5.96 (m, 1 H), 4.72-4.52 (m, 2 H), 3.34 (m,
1 H), 1.78-1.53 (m, 6 H), 1.30-0.93 (m, 5 H); 13C NMR (100 MHz, CDCl3): δ 128.9, 117.0, 108.6,
106.0, 78.1, 43.5, 40.6, 31.1, 30.1, 26.2, 26.09,26.08;
ethyl (S)-4-methyl-5-(2-nitro-1-phenylethyl)-1H-pyrrole-3-carboxylate (4q)
The title compound was prepared according to the general working procedure and purified by
column chromatography to give the product as a colorless oil in 94% yield. The regioselectivity was
determined to be >20:1 by 1H NMR analysis. [α]D20 +88.7 (c = 1.2, CH2Cl2, 91%ee); HPLC: Daicel
Chiralpak OD-H, hexane: 2-propanol = 80: 20, flow rate = 0.8 mL/min, T = 23°C, UV = 254 nm,
tR = 22.5 min (major), tR = 30.4 min (minor). 1H NMR (400 MHz, CDCl3): δ 8.68 (br, 1 H), 7.36-
7.20 (m, 6 H), 5.06-4.84 (m, 3 H), 4.24 (dd, J = 7.1 Hz, 14.2 Hz, 1H), 2.29 (s, 3 H), 1.30 (t, J = 7.1
Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 164.7, 136.1, 128.3, 126.9, 126.2, 124.9, 123.1, 117.0,
114.6, 58.6, 39.4, 13.4, 9.3;
ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra for all the products; HPLC profiles. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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Fax: 86-551-3631760. E-mail: zwang3@ustc.edu.cn
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We are grateful to the National Natural Science Foundation of China (21432009, 21672200 and
21772185). This work was supported by the Strategic Priority Research Program of the Chinese
Academy of Sciences, Grant No. XDB20000000.
REFERENCES
(1) (a) Li, C.-J. Organic Reaction in Aqueous Media—With a Focus on Carbon-Carbon Bond
Formation. Chem. Rev. 1993, 93, 2023. (b) Otto, S.; Boccaletti, G.; Engberts, J. B. F. N. A Chiral
Lewis-Acid-Catalyzed Diels-Alder Reaction. Water-Enhanced Enantioselectivity. J. Am. Chem.
Soc. 1998, 120, 4238. (c) Li, C.-J. Organic Reactions in Aqueous Media with a Focus on Carbon-
Carbon Bond Formations: A Decade Update. Chem. Rev. 2005, 105, 3095. (d) Organic Reactions
in Water: Principles, Strategies and Applications; Lindstrꢀm, U. M., Eds.; Blackwell Publishing:
Oxford, 2007. (e) Marcus, Y. Effect of Ions on the Structure of Water: Structure Making and
Breaking. Chem. Rev. 2009, 109, 1346. (f) Simon, M.-O.; Li, C.-J. Green chemistry oriented organic
synthesis in water. Chem. Soc. Rev. 2012, 41, 1415.
(2) Rideout, D. C.; Breslow R. Hydrophobic Acceleration of Diels-Alder Reactions. J. Am. Chem.
Soc. 1980, 102, 7816.
(3) (a) Breslow, R. Hydrophobic Effects on Simple Organic Reactions in Water. Acc. Chem. Res.
1991, 24, 159. (b) Azoulay, S.; Manabe, K.; Kobayashi, S. Catalytic Asymmetric Ring Opening of
meso-Epoxides with Aromatic Amines in Water. Org. Lett. 2005, 7, 4593. (c) Aplander, K.; Ding,
R.; Krasavin, M.; Marcus Lindström, U.; Wennerberg, J. Asymmetric Lewis Acid Catalysis in
Water: α-Amino Acids as Effective Ligands in Aqueous Biphasic Catalytic Michael Additions. Eur.
J. Org. Chem. 2009, 810.
(4) (a) Baron, A.; Blériot, Y.; Sollogoub, M.; Vauzeilles, B. Phenylenediamine catalysis of “click
glycosylations” in water: practical and direct access to unprotected neoglycoconjugates. Org.
Biomol. Chem. 2008, 6, 1898. (b) Butler, R. N.; Coyne, A. G.; Moloney, E. M. Organic synthesis
in water: 1,3-dipolar cycloaddition reactions at ambient temperature with aqueous suspensions of
solid reactants. Tetrahedron Lett. 2007, 48, 3501.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 22
1
2
3
4
5
6
7
8
9
(5) (a) Matsushita, M.; Kamata, K.; Yamaguchi, K.; Mizuno, N. Heterogeneously Catalyzed
Aerobic Oxidative Biaryl Coupling of 2-Naphthols and Substituted Phenols in Water. J. Am. Chem.
Soc. 2005, 127, 6632. (b) Firouzabadi, H.; Iranpoor, N.; Gholinejad, M. 2-Aminophenyl
diphenylphosphinite as a new ligand for heterogeneous palladium-catalyzed Heck–Mizoroki
reactions in water in the absence of any organic co-solvent. Tetrahedron 2009, 65, 7079. (c) Uozumi,
Y.; Nakao, R. Catalytic Oxidation of Alcohols in Water under Atmospheric Oxygen by Use of an
Amphiphilic Resin-Dispersion of a Nanopalladium Catalyst. Angew. Chem., Int. Ed. 2003, 42, 194.
(d) Shaughnessy, K. H. Hydrophilic Ligands and Their Application in Aqueous-Phase Metal-
Catalyzed Reactions. Chem. Rev. 2009, 109, 643.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Kobayashi, S.; Manabe, K. Development of Novel Lewis Acid Catalysts for Selective
Organic Reactions in AqueousMedia. Acc. Chem. Res. 2002, 35, 209. (b) Ooi, T.; Maruoka, K.
Recent Advanced in Asymmetric Phase-Transfer Catalysis. Angew. Chem., Int. Ed. 2007, 46, 4222.
(c) Kitanosono, T.; Kobayashi, S. Mukaiyama Aldol Reactions in Aqueous Media. Adv. Synth.
Catal. 2013, 355, 3095.
(7) For some recent examples of organocatalyzed Michael reactions in aqueous media, see:
(a) Zheng, Z.-L.; Perkins, B.-L.; Ni, B. Diarylprolinol Silyl Ether Salts as New, Efficient, Water-
Soluble, and Recyclable Organocatalysts for the Asymmetric Michael Addition on Water. J. Am.
Chem. Soc. 2010, 132, 50. (b) Dey, S.; Jäschke, A. Tuning the Stereoselectivity of a DNA-Catalyzed
Michael Addition through Covalent Modification. Angew. Chem., Int. Ed. 2015, 54, 11279. (c)
Akagawa, K.; Iwasaki, Y.; Kudo, K. Library Screening in Aqueous Media to Develop a Highly
Active Peptide Catalyst for Enantioselective Michael Addition of a Malonate. Eur. J. Org. Chem.
2016, 4460. (d) Zhang, K.; An, J.-Z.; Su, Y.-C.; Zhang, J.-Y.; Wang, Z.-Y.; Cheng, T.-Y.; Liu, G.-
H. Amphiphilic Hyperbranched Polyethoxysiloxane: A Self-Templating Assembled Platform to
Fabricate Functionalized Mesostructured Silicas for Aqueous Enantioselective Reactions. ACS
Catal. 2016, 6, 6229. (e) Sim, J.-H.; Song, C.-E. Water-Enabled Catalytic Asymmetric Michael
Reactions of Unreactive Nitroalkenes: One-Pot Synthesis of Chiral GABA-Analogs with AllCarbon
Quaternary Stereogenic Centers. Angew. Chem., Int. Ed. 2017, 56, 1835.
(8) (a) Kobayashi, S.; Kakumoto, K.; Mori, Y.; Manabe, K. Chiral Lewis Acid-Catalyzed
Enantioselective Michael Reactions in Water. Isr. J. Chem. 2001, 41, 247. (b) Shirakawa, S.;
ACS Paragon Plus Environment

Page 21 of 22
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1
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5
6
7
8
9
Kobayashi, S. Ag(I)-Catalyzed Michael Additions of β-Ketoesters to Nitroalkenes in Water:
Remarkable Effect of Water as a Reaction Medium on Reaction Rates. Synlett 2006, 1410. (c)
Aplander, K.;Ding, R.; Lindstrom, U. M.; Wennerberg, J.; Schultz, S. α-Amino Acid Induced Rate
Acceleration in Aqueous Biphasic Lewis Acid Catalyzed Michael Addition Reactions. Angew.
Chem. Int. Ed. 2007, 46, 4543. (d) Aplander, K.; Ding, R.; Krasavin, M.; Lindstrom, U. M.;
Wennerberg, J. Asymmetric Lewis Acid Catalysis in Water: α-Amino Acids as Effective Ligands
in Aqueous Biphasic Catalytic Michael Additions. Eur. J. Org. Chem. 2009, 810.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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44
45
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50
51
52
53
54
55
56
57
58
59
60
(9) (a) Bonollo, S.; Lanari, D.; Pizzo, F.; Vaccaro, L. Sc(III)-Catalyzed Enantioselective Addition
of Thiols to r,β-Unsaturated Ketones in Neutral Water. Org. Lett. 2011, 13, 2150. (b) Kitanosono,
T.; Sakai, M.; Ueno, M.; Kobayashi, S. Chiral-Sc catalyzed asymmetric Michael
addition/protonation of thiols with enones in water. Org. Biomol. Chem. 2012, 10, 7134.
(10) (a) Buriak, J. M. Organometallic Chemistry on Silicon and Germanium Surfaces. Chem. Rev.
2002, 102, 1271; (b) Wayner, D. D. M.; Wolkow, R. A. Organic modification of hydrogen
terminated silicon surfaces. J. Chem. Soc., Perkin Trans. 2, 2002, 23; (c) Bent, S. F. Attaching
Organic Layers to Semiconductor Surfaces. J. Phys. Chem. B 2002, 106, 2830.
(11) (a) Likhosherstov, A. M.; Filippova, O. V.; Peresada, V. P.; Kryzhanovskii,S.A.; Vititnova,
M.B.;Kaverina, N.V.; Reznikov, K. M. Synthesis and Antiarrhythmic Activity of 2-(2'-R-2'-
Hydroxyethyl)-1,2,3,4-tetra-hydro-pyrrolo-[1,2-a]pyrazines. Pharm. Chem. J. 2003, 37, 6; (b)
Seredenin, S. B.; Voronina, T.A.; Beshimov,A.; Peresada,V. P.; Likhosherstov, A. M. RU 2099055,
1997; (c) Seredenin, S. B.; Voronina, T.A.; Likhosherstov, A. M.; Peresada, V. P.; Molodavkin, G.
M.; Halikas, J. A. US 5378846, 1995, 10 pp; (d) Peresada, V. P.; Medvedev,O. S.; Likhosherstov,
A. M.; Skoldinov, A. P. Khim.-Farm. Zh. 1987, 21, 1054.
(12) (a) Guo F.-F.; Chang, D.-L.; Lai, G.-Y.; Zhu, T.; Xiong, S.-S.; Wang, S.-J.; Wang, Z.-Y.
Enantioselective and Regioselective Friedel–Crafts Alkylation of Pyrroles with Nitroalkenes
Catalyzed by a Tridentate Schiff Base–Copper Complex. Chem. Eur. J. 2011, 17, 11127. (b) Brown,
J. W.; Keung, W.; Li, Z.; Tyhonas, J. (Takeda Pharmaceutical Company, Osaka), WO
2010/111634A2, 2010.
(13) Trost, B.M.; Müller, C. Asymmetric Friedel-Crafts Alkylation of Pyrroles with Nitroalkenes
Using a Dinuclear Zinc Catalyst. J. Am. Chem. Soc. 2008, 130, 2438.
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Page 22 of 22
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5
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7
8
9
(14) (a) Wang, Y.; Zhu, D.-P.; Tang, L.; Wang, S.-J.; Wang, Z. Y. Highly Efficient Amide Synthesis
from Alcohols and Amines by Virtue of a Water-Soluble Gold/DNA Catalyst. Angew. Chem., Int.
Ed. 2011, 50, 8917. (b) Yang, Y.; Bao, Y.-J.; Guan, Q.-Q.; Sun, Q.; Zha, Z.-G.; Wang, Z.-Y.
Copper-catalyzed S-methylation of sulfonyl hydrazides with TBHP for the synthesis of methyl
sulfones in water. Green Chem. 2017, 19, 112. (c) Liu, L.- Y.; Wang, Z.-Y. Metal-free
Intramolecular Amino-acyloxylation of 2-Aminostyrene with Carboxylic acid for the Synthesis of
3-Acyloxyl indolines in Water. Green Chem. 2017, 19, 2076.
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43
44
45
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47
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50
51
52
53
54
55
56
57
58
59
60
(15) (a) Lai, G.-Y.; Guo, F.-F.; Zheng, Y.-Q.; Fang, Y.; Song, H.-G.; Xu, K.; Wang, S.-J.; Zha, Z.-
G.; Wang, Z.-Y. Highly Enantioselective Henry Reaction in Water Catalyzed by a Copper-Tertiary
Amine Complex and Application to the Synthesis of (S)-N- trans-Feruloyl Octopamine. Chem. -
Eur. J. 2011, 17, 1114. (b) Xu, K.; Lai, G.-Y.; Zha, Z.-G.; Pan, S.-S.; Chen, H.-W.; Wang, Z.-Y. A
Highly anti-Selective Asymmetric Henry Reaction Catalyzed by Chiral Copper Complex and
Applications to the Syntheses of (+)-Spisulosine and a Pyrroloisoquinoline Derivative. Chem. - Eur.
J. 2012, 18, 12357. (c) Li, Y.-N.; Huang, Y.-K.; Gui, Y.; Sun, J.-N.; Li, J.-D.; Zha, Z.-G.; Wang,
Z.-Y. Copper-Catalyzed Enantioselective Henry Reaction of β,γ-Unsaturated α-Ketoesters with
Nitromethane in Water. Org. Lett. 2017, 19, 6416.
(16) (a) Li, C.; Guo, F.-F.; Xu, K.; Zhang, S.; Hu, Y.-B.; Zha, Z.-G.; Wang, Z.-Y. Copper-Catalyzed
Enantioselective Friedel-Crafts Alkylation of Pyrrole with Isatins. Org. Lett. 2014, 16, 3192. (b)
Sun, J.-N.; Hu, Y.-B.; Li, Y.-N.; Zhang, S.; Zha, Z.-G.; Wang, Z.-Y. Copper-Catalyzed
Chemoselective and Enantioselective Friedel-Crafts 1,2-Addition of Pyrrole with β,γ-Unsaturated
α-Ketoesters. J. Org. Chem. 2017, 82, 5102.
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