(L)-Prolinamide imidazolium hexafluorophosphate ionic liquid as an efficient reusable organocatalyst for direct asymmetric aldol reaction in solvent-free condition

Article abstract of DOI:10.1039/c6ra23652a

We have designed a new hydrophobic ionic liquid derived from bromoester of trans-4-hydroxy-(l)-prolinamide and N-methylimidazole. (l)-Prolinamide imidazolium hexafluorophosphate ionic liquid (2 mol%) found to be an excellent organocatalyst for direct asymmetric aldol reaction between 4-nitrobenzaldehyde and cyclohexanone using acetic acid (2 mol%) as an additive at -15 °C in solvent-free condition, the aldol product was afforded in excellent yield with diastereomeric ratio (anti/syn; 97:3) and 94% ee of anti-aldol product. Ionic liquids can catalyze the direct aldol reaction between benzaldehyde derivatives and cycloalkanones and the best dr (anti/syn; 99.9/0.01) and 99% ee was obtained for aldol product of 2-trifluoromethyl benzaldehyde and cyclohexanone. (l)-Prolinamide imidazolium hexafluorophosphate ionic liquid was reused up to 6 continuous cycles without decrease in the conversion of the product with 92% ee and found to be superior than its counterpart trans-4-hydroxy-(l)-prolinamide. Continuous cycle experiments do not require isolation of the catalyst after each cycle. The results of reusability of the ionic liquid catalyst were found to be better than most of other reported reusable catalysts.

Full text of DOI:10.1039/c6ra23652a

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DOI: 10.1039/C6RA23652A
(L)-Prolinamide imidazolium hexafluorophosphate ionic liquid as an
efficient reusable organocatalyst for direct asymmetric aldol reaction in
solvent-free condition
Geeta Devi Yadav and Surendra Singh*
Department of Chemistry, University of Delhi, Delhi, Indiaꢀ110007
Email:ssingh1@chemistry.du.ac.in
Abstract: We have designed a new hydrophobic ionic liquid derived from bromoester of transꢀ4ꢀ
hydroxyꢀ(L)ꢀprolinamide and Nꢀmethylimidazole. (L)ꢀProlinamide imidazolium hexafluorophosphate
ionic liquid (2 mol%) found to be an excellent organocatalyst for direct asymmetric aldol reaction
between 4ꢀnitrobenzaldehyde and cyclohexanone using acetic acid (2 mol%) as an additive at ꢀ15°C
in solventꢀfree condition, the aldol product was afforded in excellent yield with diasteromeric ratio
(anti/syn; 97:3) and 94% ee of antiꢀaldol product. Ionic liquid can catalyze the direct aldol reaction
between benzaldehyde derivatives and cycloalkanones and best dr (anti/syn; 99.9/0.01) and 99% ee
was obtained for aldol product of 2ꢀtrifluoromethyl benzaldehyde and cyclohexanone. (L)ꢀ
Prolinamide imidazolium hexafluorophosphate ionic liquid was reused up to 6 continuous cycles
without decrease in the conversion of the product with 92% ee and found to be superior than its
counterpart transꢀ4ꢀhydroxyꢀ(L)ꢀprolinamide. Continuous cycle experiments do not require isolation
of the catalyst after each cycle. The results of reusability of the ionic liquid catalyst were found to be
better than most of other reported reusable catalysts.
Keywords: Organocatalysis/ Direct asymmetric aldol reactions / (L)ꢀProlinamide / Ionic
liquid / Continuous cycles
Introduction
The aldol reaction is recognized as one of the most powerful carbonꢀcarbon bondꢀforming
reactions in modern organic synthesis. It provides an atomꢀeconomic approach to βꢀhydroxyl
carbonyls, which make up a large family of chiral intermediates for the synthesis of
biologically active substances and natural product.1 Since the early reports in the 1970s that
the Lꢀproline catalysed intramolecular aldol reactions2a,b later the pioneering work by List et
al. in 2000.2c,d After these reports numerous prolineꢀderived organocatalysts such as proline
analogues,3 acyclic amino acids,4 different types of prolinamides,5–13 prolinethioamides,14
sulfonamides,15 chiral amines,16 organic salts17 were exploited as organocatalysts for direct
asymmetric aldol reaction. The organocatalyst is usually used for direct asymmetric aldol
reaction in a substantial quantity, in some cases up to 30 mol%, its recovery and reuse is vital
for reduce the cost and to facilitate the separation of the product from the catalyst. Several
research groups are attentive to develop a recoverable organocatalysts for direct asymmetric
aldol reaction.18 Immobilization of modified proline derivatives are desirable due to their
nonꢀcommercial viability and their high reactivity.
In our ongoing research on development of organocatalyst for asymmetric Dielsꢀalder
reaction and direct asymmetric aldol reaction.19 We recently reported the transꢀ4ꢀhydroxyꢀ
(L)ꢀprolinamide (1) as organocatalyst for aldol reaction between aromatic aldehydes and
cycloalkanes under solvent free conditions.20 Herein, we wish to report synthesis of
imdidazolium ionic liquids from bromoester of transꢀ4ꢀhydroxyꢀ(L)ꢀprolinamide and Nꢀ
methylimidazole and their catalytic activity in direct asymmetric aldol reaction.
1

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N
An
N
O
O
HO
O
O
N
HN
N
H
HN
H
2; An = Br
3; An = PF6
1
Figure 1. Prolinamide catalysts for direct asymmetric aldol reaction.
Results and discussion
Prolinamide imdazolium ionic liquids 2 and 3 were synthesized according to scheme
1. First, transꢀ4ꢀhydroxyꢀ(S)ꢀproline 4 was protected as Nꢀboc protecting group in
quantitative yield. NꢀBocꢀtransꢀ4ꢀhydroxyꢀ(S)ꢀproline
5
was treated with (S)ꢀ1ꢀ
phenylethylamine, in presence of triethylamine and ethylchloroformate, gave corresponding
Nꢀbocꢀprolinamide 6 in 81% yield. The esterification of compound 6 with 5ꢀbromovleric acid
in the presence of DCC and DMAP in dichloromethane gave the product 7 in a 94% yield.
The compound 8 was synthesised by the reaction of Nꢀmethyl imidazole and compound 7,
which affords Nꢀboc protected imidazolium bromide 8 in 97% yield. The bromide anion of
the ionic liquid 8 was exchanged by KPF6 to hexafluorophosphate anion in 86% yield.
Deprotection of Nꢀboc group in compounds 8 and 9 by TFA in dichloromethane at room
temperature gave ionic liquid (IL) 2 and 3.
In our initial investigation, the direct asymmetric aldol reaction between 4ꢀ
nitrobenzaldehyde 10 and cyclohexanone using ionic liquid 3 (10 mol %) and acetic acid (10
mol %) as additives at room temperature gave >99 % conversion and 29% enantiomeric
excess (ee) of product anti 11 with poor diastereoselectivity (Table 1, entry 1). Decreasing of
the reaction temperature to ꢀ15°C, improved the diastereomeric ratio (dr; anti/syn; 94:6) and
ee (96%) of the product antiꢀ11 (Table 1, entries 2). We also varied the catalyst loading and
even though at low catalyst loading (2 mol%) with additive acetic acid (2 mol%), product
antiꢀ11 was obtained in excellent yield with 94% ee and dr (anti/syn; 97:3) after 24 h (Table
1, entry 3ꢀ4). We also compared the catalytic result with organocatalyst 1 with ionic liquid 3
(IL 3) under identical conditions and the organocatalyst 1 was found to be more reactive but
better ee for product antiꢀ11 was observed with IL 3 (Table 1, entry 5). IL 2 gave the aldol
product in poor yield (39%) with 76% ee of antiꢀ11 (Table 1, entry 6).
2

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HO
HO
O
HO
(S)-1-phenylethylamine
O
O
(Boc)2O
DCM
N
OH
N
Et3N, ClCO2Et,
r.t. 6 h, 81%
N
HN
OH
THF/H2O, r.t.,12 h
quantitative
H
Boc
Boc
6
4
5
DCC, DMAP
DCM,r. t. 3 h
94%
Br(CH2)4COOH
N
Br
N
Br
N
O
O
O
O
O
HN
N
O
H
N
HN
N
Boc
Boc
8
80 °C 10 min, 97%
7
KPF6/H2O
86%
TFA:DCM, 1:1
6 h, 85-87%
N
An
N
PF6
N
N
O
O
O
O
O
O
N
HN
N
HN
H
Boc
2; An = Br
3; An = PF6
9
Scheme 1. Synthesis of ionic liquids (IL) 2 and 3.
Table 1. Optimization of reaction conditions for direct asymmetric aldol reaction.a
CHO
O
OH
O
OH O
Catalyst
+
CH3COOH
Neat
O2N
O2N
NO2
10
11-anti
11-syn
Entry Organocatalyst
Catalyst
loading (mol
Time (h) Yieldb (%)
dr
ee (%)
(anti:syn) c
(anti)d
%)
10
10
5
2
2
1
2
3
4
5
6
3
3
3
3
1
2
6
>99
>99
>99
99
>99
39
59:41
94:6
96:4
97:3
93:7
85:15
29e
96
91
94
92
76
12
12
24
8
2
24
a Organocatalyst (2ꢀ10 mol %), CH3COOH (2ꢀ10 mol %), cyclohexanone (3 mmol) and 4ꢀnitrobenzaldehyde (1
mmol) were stirred at 15 °C for specified time.
−
b Conversion was determined by HPLC using response factor for 4ꢀnitrobenzaldehyde 10 and product 11.
c
Diastereomeric ratio (dr) (anti/syn) and enantiomeric excess (ee) were determined by HPLC using chiralpak
ADꢀH column.
d
The absolute configuration was determined by comparing the specific rotation of product antiꢀ11 with
literature values and found to be (1’S, 2R).
e Reaction carried out at room temperature.
3

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We also compared our organocatalyst IL 3 with other reusable organocatalysts
reported in literature for the direct asymmetric aldol reaction between 4ꢀnitrobenaldehyde and
cyclohexanone are shown in SI Table 1. The results show that IL3 was found to be better
catalyst in terms of catalyst loading and turnover frequency than the most of the reported
reusable catalysts.
We have investigated the asymmetric direct aldol reaction between substituted
benzaldehydes and cyclohexanone catalyzed by IL 3 (2 mol%) and additive CH3COOH (2
mol%) at
−
15 °C in solventꢀfree conditions. All the benzaldehyde derivatives gave the anti
diastereomer as major product. Benzaldehyde afforded aldol product in a 60% yield with
diastereomeric ratio of anti:syn (91/9) with 98% ee of anti diastereomer and bulkier
naphthaldehyde improved the anti:syn ratio but ee was slightly decreased (Table 2, entry 1
and 2). Electron withdrawing group (EWG) such as nitro on benzaldehyde improved the
reactivity and 2ꢀnitrobenzaldehyde gave 97% ee (Table 2, entry 3). 4ꢀHalogenated
benzaldehydes were found to be less reactive with excellent ee and dr. The order of reactivity
of 4ꢀhalogenated benzaldehydes (F<Cl<Br) was increasing when electronegativity of halogen
is decreasing due to enhancement of electrophilicity of carbonyl carbon of halobenzaldehydes
(Table 2, enties 5, 7, and 9). 2ꢀHalobenzaldehydes gave the corresponding aldol products in
88ꢀ90% yields and 91ꢀ97% ee (Table 2, entries 4, 6, and 8). Electron donating group (EDG)
like methoxy on benzaldehyde, found to be less reactive compared to derivatives of EWG.
The EWG’s enhance the electrophilicity of carbonyl carbons in aldehydes which facilitate the
reaction, while EDG’s lessen the electrophilicity of carbonyl carbons. 4ꢀ
Methoxybenzaldehyde was found to be least active and afforded only 5% of the product but
by increasing the catalyst loading was increased to 5 mol% and 25% yield of the product was
obtained (Table 2, entries 11 and 12). In case of 2ꢀ(trifluoromethyl)benzaldehyde, exclusively
afforded anti product in 99% ee (Table 2, entry 13).
Table 2. Aldol reaction of cyclohexanones with substituted benzaldehydes catalysed by IL
3.a
O
OH
O
O
Catalyst 3 (2 mol%)
Ar
H
Ar
Neat, -15 °C
CH3COOH,
Entry
Ar
Time [h]
Yieldb (%)
dr (anti:syn) c ee (%)
(anti)d
1
2
3
4
5
6
7
8
9
Phenyl
24
48
17
18
24
18
26
18
26
40
60
25
87
88
49
90
74
90
84
23
91:9
98:2
96:4
97:3
98:2
95:5
98:2
97:3
97:3
99:1
98
93
97
91
93
97
97
97
98
91
1ꢀNapthyl
2ꢀNO2C6H4
2ꢀFC6H4
4ꢀFC6H4
2ꢀClC6H4
4ꢀClC6H4
2ꢀBrC6H4
4ꢀBrC6H4
2ꢀOMeC6H4
10
4

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11
12
13
4ꢀOMeC6H4
4ꢀOMeC6H4
2ꢀCF3C6H4
4ꢀCF3C6H4
48
48
17
17
5
63:37
99.8:0.2
100: 0
97:3
ND
25
69
87
52e
99
14
91
a
IL 3 (0.02 mmol, 2 mol%), CH3COOH (0.02 mmol, 2 mol%), cyclohexanone (3 mmol) and substituted
benzaldehyde (1 mmol) were stirred at ꢀ15 °C for specified time.
b Isolated yield after purification by column chromatography.
c Diastereomeric ratios (dr) were determined by 1HꢀNMR of crude products.
d Enantiomeric excess (ee) was determined by HPLC using chiralpak ADꢀH and chiralcel ODꢀH columns.
e 5 mol% catalyst was used.
We have also studied the direct asymmetric aldol reaction between 2ꢀ and 4ꢀ
substituted benzaldehydes with cyclopetanone catalyzed by IL 3 (2 mol%) at ꢀ15 °C in
solventꢀfree conditions (Table 3). The reactivity of benzaldehydes having EWG’s was faster
than the EDG’s. In case of 4ꢀsubstituted benzaldehydes anti aldol products were obtained as
major diastereomers while syn diastereomers were obtained with 2ꢀsubstituted benzaldehydes
except 2ꢀnitrobenzaldehyde (Table 3, entries 1ꢀ8). The better ee was obtained for anti
diasteromers of the aldol products than syn diastereomers. The reactivity of 4ꢀmethoxy was
found to be poor and but by increasing the catalyst loading to 5 mol% increased the yield
(Table 3, entries 8 and 9).
Table 3. Aldol reaction of cyclopentanone with substituted benzaldehydes catalysed by IL
3.a
O
O
OH
O
Catalyst 3 (2 mol%)
Ar
H
Ar
Neat, CH3COOH,
-15 °C
Entry
Ar
Time (h)
Yieldb (%)
dr (anti:syn)c ee (%)
(anti/syn)d
99/28
1
2
3
4
5
6
7
8
2ꢀNO2C6H4
4ꢀNO2C6H4
2ꢀFC6H4
4ꢀFC6H4
2ꢀClC6H4
4ꢀClC6H4
2ꢀOMeC6H4 48
4ꢀOMeC6H4 48
4ꢀOMeC6H4 44
30
30
40
40
38
38
71
66
76
69
37
72
33
7
55:45
50:50
43:57
72:28
40:60
54:46
21:79
72:28
44:56
66/40
81/26
82/20
99/45
84/26
97 /33
70/20
81/8e
9
64
a
IL 3 (0.02 mmol, 2 mol%), CH3COOH (0.02 mmol, 2 mol%), cyclopentanone (3 mmol) and 4ꢀ
nitrobenzaldehyde (1 mmol) were stirred at ꢀ15 °C for specified time.
b Isolated yield after purification by column chromatography.
c Diastereomeric ratios were determined by 1HꢀNMR of crude products.
d The ee was determined by HPLC using chiralpak ADꢀH, and chiralcel ODꢀH columns.
e Reaction carried out using 5 mol% of the catalyst
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The reusability performance of the IL 3 (2 mol%) was carried out for the asymmetric
aldol reaction of 4ꢀnitrobenzaldehyde 10 (1 mmol) and cyclohexanone (3 mmol) using acetic
acid (2 mol%) as additive at ꢀ15°C (Table 4). The reaction was monitored on TLC and
HPLC, after complete conversion of 4ꢀnitrobenzaldehyde 10, 4ꢀnitrobenzaldehyde 10 (1
mmol) and cyclehexanone (3 mmol) were added to the reaction mixture without any additive
and catalyst. This procedure was repeated for 6 continuous cycles and afforded aldol products
in overall >99% conversion of the product with anti/syn 96:4 with 92% ee of product 11-anti
and total turnover number (TON) of the catalyst was found to be more than 346 (Table 4,
entry 7 and Figure 2). The advantages of continuous cycle for the reuse of the catalyst are: (i)
IL3 and catalytic product of the aldol reaction are polar so it’s difficult to separate catalyst
from the product by using the different solvents therefore use of continuous cycle is
beneficial, (ii) It enhances economic viability of the process because it does not require
separation of the catalyst after completion of each cycle which save the cost of the manpower
and solvents and (iii) the product is stable during the reaction even though we are stirring the
reaction up to 7 cycles. Similar strategy was used by List and coꢀworkers in cyanosilylation
of aldehydes.20 We also compared the catalysis of IL3 in low loading (0.4 mol%) in identical
reaction conditions and afforded product in >99% yield and anti/syn 95:5 with 85% ee of
product 11ꢀanti after 4.5 days and these results are found to be poor in terms of ee than the
continuous use of the IL 3. We also conducted the aldol reaction using catalyst 1 (2 mol%)
under identical conditions to compare the reusability in continuous cycle. Catalyst 1 afforded
the desired product anti-11 in 97% yield and 96% ee but reaction took 65 h for completion
of a 4th continuous cycle. The overall TON and TOF was found to be better for the catalyst 3
compared to the catalyst 1. The hydrophobic nature of the ionic liquid unit of the catalyst 3
maintains the catalytic activity at dilution of the catalyst concentration in continuous cycle.
Figure 2. Reusability of IL 3 in continuous cycle
6

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Table 4. Reusability of IL 3 in continuous cycle for asymmetric aldol reaction.a
CHO
O
OH
O
Catalyst 3
CH3COOH
Neat
O2N
NO2
10
11-anti
Cycle
Time (h)
20 (8)e
20 (24)
20 (48)
24 (65)
24
Conversion (%)b
>99 (>99)
>99 (96)
>99 (96)
>99 (97)
>99
dr (anti:syn)c
97:3 (93:7)
91:9 (95:5)
95:5 (96:4)
96:4 (96:4)
96:4
ee (%) (anti)c,d
1
2
3
4
5
6
7
88 (92)
88 (93)
93 (96)
92 (96)
92
24
24
>99
>99
96:4
96:4
92
92
aCatalyst 3 (0.02 mmol, 2 mol%), CH3COOH (0.02 mmol, 2 mol%), cyclopentanone (3 mmol) and 4ꢀ
nitrobenzaldehyde (1 mmol) were stirred at ꢀ15 °C for specified time.
bConversion was determined by HPLC using response factor for 4ꢀnitrobenzaldehyde 10 and product 11.
cDiastereomeric ratio (dr) and enantiomeric excess (ee) were determined by HPLC using chiralpak ADꢀH
column.
dThe absolute configuration was determined by comparing optical rotation of product 11ꢀanti with literature and
found to be (1’S, 2R).
eResults in parenthesis are for catalyst 1 under identical reaction conditions.
f Turn over frequency (TOF) for catalyst 3 = 2.22 hꢀ1 and for catalyst 1 = 1.34 hꢀ1; turn over number (TON) for
catalyst 3 = 346 and for catalyst 1 = 194.5.
Experimental Section
General
Benzaldehyde derivatives, cyclohexanone and cyclopentanone were purchased from
commercial source and used as such. Proton and carbon nuclear magnetic resonance spectra
(1H and 13C NMR, respectively) were recorded on 400 MHz (operating frequencies: 1H,
400.13 MHz; 13C, 100.61 MHz) JeolꢀFTꢀNMR spectrometers at ambient temperature. The
chemical shifts ( ) for all compounds are listed in parts per million (ppm) downfield from
tetramethylsilane using the NMR solvent as an internal reference. The reference values used
1
for deuterated chloroform (CDCl3) were 7.26 and 77.00 ppm for H and 13C NMR spectra,
respectively. HRMS analysis was carried out using QSTAR XL Pro system microTOFꢀQꢀII.
The reaction was monitored by thin layer chromatography was carried out using Merck
Kieselgel 60 F254 silica gel plates. Compounds were purified by column chromatography
separations were performed using silica gel 230–400 mesh. The enantiomeric excess was
determined on Shimadzu LCꢀ2010HT using chiralcel ODꢀH, and chiralpak ADꢀH columns.
Infrared spectra were recorded on a PerkinꢀElmer FTꢀIR spectrometer. Optical rotations were
taken
using
Rudolph
digipol
polarimeter.
(2S,4R)ꢀ1ꢀ(tertꢀButoxycarbonyl)ꢀ4ꢀ
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hydroxypyrrolidineꢀ2ꢀcarboxylic acid (5) and (2S, 4R)ꢀtertꢀbutylꢀ4ꢀhydroxyꢀ2ꢀ((S)ꢀ1ꢀ
phenylethylcarbamoyl)pyrrolidineꢀ1ꢀcarboxylate (6) were synthesised according to our
1
earlier report.19a All the unknown compounds were characterized by H, 13C NMR and
1
HRMS. Aldol products were characterized by HꢀNMR and compared compared with our
1
earlier report.19a Copy of HꢀNMR, 13CꢀNMR and HPLC chromatogram are given in
supporting information.
(2S,4R)-tert-Butyl2-((S)-1-phenylethylcarbamoyl)-4-(5-bromopentanoyloxy)pyrrolidine-
1-carboxylate (7)
5–bromovaleric acid (0.712 g, 3.94 mmol) was added to a solution of DCC (0.812 g, 3.94
mmol) and DMAP (0.0356 g, 0.292 mmol) in CH2Cl2 24 mL) at 0 °C and compound 6 (1.02
°
g, 3.07 mmol) was added in 10 min. The reaction mixture was stirred at 0 C for 1h. The
reaction progress was monitored by TLC. The combined organic washings were evaporated,
the residue was purified by column chromatography on silica gel (eluent: EtOAc/Hexane 8/2)
to afford the ester 7as colourless liquid. Yield 1.52 g (94 %); [α]D25= −55.1 (c 1.2, CHCl3);IR
(K Br): 3297, 2975, 1735, 1698, 1405, 1163 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ= 7.24–7.19
(m, 5H), 5.20–5.17 (m, 1H), 5.09–4.96 (m, 1H), 4.27 (t, J = 7.63 Hz, 1H), 3.58–3.48 (m, 1H),
3.34 (t, J = 6.10 Hz, 2H), 2.48 (t, J = 6.87 Hz, 1H), 2.27 (t, J = 7.63 Hz, 2H), 1.86–1.68 (m,
6H), 1.42 (s, 9H), 1.33–1.20 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.75, 170.21,
154.89, 142.70, 127.91 (2C), 126.38, 125.27 (2C), 80.07, 72.30, 68.79, 59.69, 57.74, 51.76,
48.21, 32.56, 32.46, 31.25, 27.66, 22.77 ppm. HRMS (ESI): m/z [M+H]+calcd for
C23H34BrN2O5: 497.1651; found: 497.1661.
(2S,4R)-tert-Butyl2-((S)-1-phenylethylcarbamoyl)-4-(pentanoyloxy)pyrrolidine-1-
carboxylate (1-methyl-1H-imidazol-3-ium) bromide (8)2
A mixture of ester 7 (3.04 g, 6.14mmol) and 1ꢀmethylꢀ1Hꢀimidazole (2.28 g, 27.8mmol) was
heated at 80 °C for 10 min, cooled to r.t. and washed thoroughly with Et2O (5×40 mL). The
residue was dissolved in MeOH (6 mL), then Et2O (60 mL) was added to the solution. The
separated oil was dried under reduced pressure for 1 h to afford bromide 8 as colourless
liquid. Yield 3.44 g (97%); [α]D20 = −69.6 (c 0.6, CHCl3); IR (K Br): 3302, 2927, 1728, 1691,
1
1408, 1053, 842 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 10.33 (brs, 1H), 7.43 (s, 1H), 7.33–
7.16 (m, 7H), 5.17–5.13 (m, 1H), 5.07–4.95 (m, 1H), 4.43 (t, J = 7.63 Hz, 2H), 4.38–4.28 (m,
1H), 4.01 (s, 3H), 3.70–3.49 (m, 2H), 2.53–2.33 (m, 4H), 1.93 (quin, J = 7.63 Hz, 2H), 1.62
(quin, J = 6.87 Hz, 2H), 140 (s, 9H), 1.35–1.31 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ
=172.14, 170.92, 154.38, 143.57, 137.06, 128.33 (2C), 126.28, 125.95 (2C), 123.32, 122.23,
80.52, 72.50, 58.88, 52.07, 52.07, 49.35, 48.83, 36.43, 33.09, 29.29, 28.10, 22.17, 21.13 ppm.
+
HRMS (ESI): m/z [M]+calcd for C27H39N4O5 : 499.2915; found: 499.2916.
(2S,4R)-tert-Butyl-2-((S)-1-phenylethylcarbamoyl)-4-(pentanoyloxy)pyrrolidine-1-
carboxylate (1-methyl-1H-imidazol-3-ium)hexafluorophosphate (9)
A solution of KPF6 (552 mg, 3mmol) in water (3 mL) was added to a stirred solution of
bromide 8 (1.73 g, 3.0mmol) in water (9 mL). The precipitate was filtered off, washed with
water (3×9 mL) and dried under reduced pressure (0.5 Torr) for 1 h to afford
8

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hexafluorophosphate 9 as colourless solid. Yield 1.66 g (86 %); [α]D25 = −39.7 (c1.5, CHCl3);
1
IR (K Br): 3294, 2931, 1727, 1655, 1449, 1199, 841cmꢀ1. H NMR (400 MHz, CDCl3): δ =
8.44 (s, 1H), 7.26–7.15 (m, 8H), 5.17–5.12 (m, 1H), 5.02–4.91 (m, 1H), 4.33–4.24 (m, 1H),
4.05 (t, J = 7.63 Hz, 2H), 3.77 (s, 3H), 3.67–3.39 (m, 2H), 2.28–2.26 (m, 3H), 1.85–1.80 (m,
3H), 1.54 (t, J = 7.63 Hz, 2H), 1.40 (s, 9H), 1.35–1.31 (m, 3H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.26, 171.14, 154.24, 143.43, 135.56, 128.34 (2C), 126.91, 125.71 (2C),
123.44, 122.05, 80.61, 72.51, 59.02, 53.36, 49.17, 48.71, 36.47, 35.80, 34.07, 32.83, 27.92,
21.89, 20.81 ppm.19F NMR (376 MHz): δ = −71.63 (d, JPꢀF = 710.62 Hz) ppm; 31P NMR (161
MHz): δ = −143.64 (heptet, JPꢀF= 715.50 Hz) ppm. HRMS (ESI): m/z [M]+calcd for
+
C27H39N4O5 : 499.2915; found: 499.2917.
(2S,4R) -2-((S)-1-Phenylethylcarbamoyl)-4-(pentanoyloxy)pyrrolidine (1-methyl-1H-
imidazol-3-ium)bromide (2)1
The bromide 8 (1.79 g, 3.1mmol) was dissolved in dry dichloromethane (2.5 mL) and
trifluoroacetic acid (2.5 mL) was added, then stirred at room temperature for 6 h. Reaction
mixture was concentrated in vacuo, dissolved in H2O (10 mL), and the pH was adjusted to ~
8 by adding 10% NaOH. The product was then extracted with dichloromethane (3x10 mL),
dried over MgSO4, and concentrated in vacuo yielding hydroscopic colourless liquid (2).
Yield 1.48 g (87%); [α]D25= −18.6 (c1.8, CH3OH); IR (K Br): 3419, 2924, 1684, 1457, 1052,
842 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 9.73 (brs, 1H), 9.42 (s, 1H), 7.35—7.32 (m, 7H),
5.23–5.12 (m, 1H), 4.91–4.71 (m, 2H), 4.20–4.15 (m, 2H), 3.88 (s, 3H), 3.56–3.40 (m, 2H),
2.35–2.28 (m, 2H), 2.10–2.03 (m, 1H), 1.86–1.78 (m, 3H), 1.66–1.54 (m, 2H), 1.39 (d, J =
6.87 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.32, 165.90, 143.50, 137.02, 128.01
(2C), 126.52, 125.39 (2C), 123.00, 121.83, 72.79, 57.93, 51.74, 50.61, 49.39, 48.75, 35.69,
+
32.75, 28.67, 21.88, 20.47 ppm. HRMS (ESI): m/z [M]+calcd for C22H31N4O3 : 399.2391;
found: 399.2385.
(2S,4R)-2-((S)-1-phenylethylcarbamoyl)-4-(pentanoyloxy)pyrrolidine
(1-methyl-1H-
imidazol-3-ium)hexafluorophosphate (3)1
The compound 9 (1.35 g, 2.1 mmol) was dissolved in dry dichloromethane (2.0 mL) and
trifluoroacetic acid (2.0 mL) was added, then stirred at room temperature for 6 h. Reaction
mixture was concentrated in vacuo, dissolved in H2O (10 mL), and the pH was adjusted to ~
8 by adding 10% NaOH. The product was then extracted with dichloromethane (3x10 mL),
dried over MgSO4, and concentrated in vacuo yielding hydroscopic colourless liquid (3).
Yield 0.969 g (85%); [α]D25= −72.1 (c 0.69, CH3OH); IR (KBr): 3436, 2927, 1677, 1046, 841
cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 9.17−9.15 (bs, 2H), 7.76 (d, J = 1.53 Hz, 1H), 7.03 (s,
1H), 7.33—7.21 (m, 5H), 5.24 (t, J = 4.20 Hz, 1H), 4.93 (quintet, J = 7.63 Hz, 1H), 4.41 (m,
1H), 4.17 (t, J = 7.63 Hz, 2H), 3.84 (s, 3H), 3.56–3.52 (m, 1H), 3.38–3.31 (m, 1H), 2.54–2.49
(m, 1H), 2.34 (t, J = 7.63 Hz, 2H), 2.03–1.96 (m, 1H), 1.80 (quintet, J = 7.63 Hz, 2H), 1.49
(quintet, J = 7.63 Hz, 2H), 1.38 (d, J = 7.63 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ =
172.04, 166.19, 144.05 (CH), 136.69 (CH), 128.48 (2xCH), 126.96 (CH), 125.77 (2xCH),
123.72 (CH), 122.33 CH), 73.07 (CH), 58.03 (CH), 50.62 (CH2), 48.77 (CH), 48.46 (CH2),
35.77 (CH3), 35.51 (CH2), 32.57 (CH2), 28.79 (CH2), 22.46 (CH3), 20.70 (CH2) ppm.19F
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NMR (376 MHz):δ= −72.30 (d, JPꢀF = 710.34 Hz) ppm;31P NMR (161 MHz): δ= −144.12
(heptet, JPꢀF= 708.44 Hz) ppm. HRMS (ESI): m/z [M]+calcd for C22H31N4O3 : 399.2391;
+
found: 399.2390.
General procedure for asymmetric aldol reaction
The organocatalyst (IL-3) (10.8 mg, 0.02 mmol), cyclohexanone (0.310 mL, 3 mmol) and
acetic acid (1.1 ꢀL, 0.02 mmol) was stirred for 20 min at −15 °C, then 4ꢀnitrobenzaldehyde
10 (151 mg, 1 mmol) was added. The reaction mixture was stirred for a specified reaction
time period at same temperature. The crude aldol product was purified by flash column
chromatography on silica gel (hexane/ethyl acetate (3/1)). The diastereomeric ratio was
determined by 1HꢀNMR of the crude product. The ee of the aldol product was determined by
HPLC using chiral column (chiralpak ADꢀH and ODꢀH) using hexane/2ꢀpropanol as mobile
phase.
(S)-2-((R)-Hydroxy(4-nitrophenyl)methyl)cyclohexanone (11) 19a
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.84 (dd,
J = 7.60, 3.2 Hz, 1H), 4.12 (s, OH, 1H), 2.64–2.52 (m, 1H), 2.48–2.41 (m, 1H), 2.34–2.26
(m, 1H), 2.08–2.02 (m, 1H), 1.81–1.78 (m, 1H), 1.66–1.45 (m, 3H), 1.36–1.26 (m, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ = 214.93, 148.49, 147.68, 127.88 (2C), 123.44 (2C), 73.97,
57.20, 42.66, 30.75, 27.71, 24.69 ppm. HPLC analysis: Chiralpak ADꢀH (Hexane/iꢀPrOH =
90/10, 1.0 mL/min, 254 nm, 25 °C): tminor = 22.6 min, tmajor = 30.9 min, ee: 94%.
Conclusions
In summary, we designed a new, efficient, and reusable organocatalyst for the direct
asymmetric aldol reaction. IL 3 was synthesised in 55% of overall yield in 6 steps. Only 2
mol% of hydrophobic IL 3 was efficiently catalysed the reaction at ꢀ15°C in solventꢀfree
conditions. The scope and limitations of the catalyst was investigated for the reaction
between benzaldehyde derivatives and cycloalkanes, gave corresponding aldol products in
25ꢀ90% yields with up to 99% ee of anti diastereomer. Poor yield of the aldol product was
obtained with methoxyꢀbenzaldehyde which can be improved by increasing the catalyst
loading. The isolation of the product from the catalyst is difficult by precipitation for this
reaction. We have used alternative method for resuse of organocatalyst (IL 3) and the catalyst
was successfully reused up to 6 continuous cycles with excellent yields of the aldol product
with 92% ee and shown better activity in continouos cycles compared to the transꢀ4ꢀhydroxyꢀ
(L)ꢀprolinamide (1).
Acknowledgements
SS acknowledges the financial assistance from Science and Engineering Research
Board (SERB), Department of Science and technology (DST), India, under scheme
Fast Track Young Scientist (SB/FT/CSꢀ020/2012). We are also thankful to University
Science Instrumentation Center (USIC), University of Delhi, India, for analytical data.
10

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Authors are thankful to DUꢀDST mass facility at USIC. GDY is thankful to CSIR for
providing Senior Research Fellowship (SRF).
References
1
(a) B. M. Kim, S. F. Williams, S. Masamune, In Comprehensive Organic Synthesis;
B. M. Trost, I. Fleming, C. H. Heathcock, Eds.; Pergamon: Oxford, 1991, pp 1–10;
(b) B. M. Trost, Science, 1991, 254, 1471—1477; (c) B. M. Trost, Angew. Chem. Int.
Ed. 1995, 34, 259—281; (d) C. Palomo, M. Oiarbide, J. M. Garciak, Chem. Soc. Rev.,
2004, 33, 65—75; (e) X. Y. Xu, Y. Z. Wang, L. F. Cun, L. Z. Gong, Tetrahedron:
Asymmetry, 2007, 18, 237—242.
2
3
(a) U. Eder, G. Sauer, R. Wiechert, Angew. Chem, Int. Ed. Engl., 1971, 10, 496—497;
(b) Z. G. Hajos, D. R. Parrish, J. Org. Chem., 1974, 39, 1615—1621; (c) B. List, R.
A. Lerner, C. F. Barbas, III. J. Am. Chem. Soc., 2000, 122, 2395—2396; (d) W. Notz,
B. List, J. Am. Chem. Soc., 2000, 122, 7386—7387.
Proline analogues: (a) J. M. Huang, X. T. Zhang, D. W. Armstrong, Angew. Chem.,
Int. Ed., 2007, 46, 9073—9077; (b) S. Chandrasekhar, B. Tiwari, B. B. Parida, C. R.
Reddy, Tetrahedron: Asymmetry, 2008, 19, 495—499; (c) D. Font, S. Sayalero, A.
Bastero, C. Jimeno, M. A. Pericás, Org. Lett., 2008, 10, 337—340; (d) F. Giacalone,
M. Gruttadauria, P. Agrigento, P. L. Meo, R. Noto, Eur. J. Org. Chem. 2010, 5696—
5704; (e) A. Armstrong, Y. Bhonoah, A. J. P. White, J. Org. Chem., 2009, 74, 5041—
5048; (f) E. Montroni, S. P. Sanap, M. Lombardo, A. Quintavalla, C. Trombini, D. D.
Dhavale, Adv. Synth. Catal., 2011, 353, 3234—3240.
4
5
Amino acid: (a) A. Bassan, W. Zou, E. Reyes, F. Himo, A. Córdova, Angew. Chem.,
Int. Ed., 2005, 44, 7028—7032; (b) A. Córdova, W. Zou, I. Ibrahem, E. Reyes, M.
Engqvist, W. W. Liao, Chem. Commun., 2005, 3586—3588; (c) M. Amedjkouh,
Tetrahedron: Asymmetry, 2007, 18, 390—395; (d) C. L. Wu, X. Q. Long, S. Li, X. K.
Fu, Tetrahedron: Asymmetry, 2012, 23, 315—328.
NꢀArylprolinamides: (a) Y. Q. Fu, Z. C. Li, L. N. Ding, J. C. Tao, S. H. Zhang, M. S.
Tang, Tetrahedron: Asymmetry, 2006, 17, 3351—3357; (b) S. Sathapornvajana, T.
Vilaivan, Tetrahedron, 2007, 63, 10253—10259; (c) Y. Q. Fu, Z. C. Li, L. N. Ding, J.
C. Tao, S. H. Zhang, M. S. Tang, Tetrahedron: Asymmetry, 2006, 17, 3351—3357;
11

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(d) J. N. Morrthy, S. Saha, Eur. J. Org. Chem., 2009, 739—748; (e) Z.ꢀH. Tzeng, H.ꢀ
Y. Chen, R. J. Reddy, C.ꢀT. Huang, K. Chen, Tetrahedron, 2009, 65, 2879—2888; (f)
S. P. Zhang, X. K. Fu, S. D. Fu, Tetrahedron Lett., 2009, 50, 1173—1176; (g) J. W.
Xu, X. K. Fu, C. L. Wu, X. Y. Hu, Tetrahedron: Asymmetry , 2011, 22, 840—850; (h)
T. Mino, A. Omura, Y. Uda, K. Wakui, Y. Haga, M. Sakamoto, T. Fugita,
Tetrahedron: Asymmetry, 2011, 22, 2024—2028; (i) P. B. Thorat, S. V. Goswami, B.
C. Khade, S. R. Bhusare, Tetrahedron Lett., 2012, 53, 6083—6086; (j) R. L. Sutar, N.
N. Joshi, Tetrahedron: Asymmetry, 2013, 24, 43—49; (k) X. R. Huang, Q. Liu, J.
Wang, J. A. Xiao, H. Yang, Tetrahedron: Asymmetry , 2014, 25, 1590—1598.
Prolinamides derived from carbohydrates: (a) J. Agarwal, R. K. Peddinti,
Tetrahedron: Asymmetry, 2010, 21, 1906—1909; (b) J. Agarwal, R. K. Peddinti, Eur.
6
7
J. Org. Chem., 2012, 6390—6406; (c) C. Shen, F. Shen, G. Zhou, H. Xia, X. Chen, X.
Liu, P. Zhang, Catal. Commun., 2012, 26, 6—10; (d) D. Miura, T. Fujimoto, A.
Tsutsui, T. Machinami, Synlett, 2013, 1501—1504.
BINAMꢀprolinamide: (a) G. Guillena, M. C. Hita, C. Najera, Tetrahedron:
Asymmetry, 2006, 17, 1493—1497; (b) G. Guillena, M. C. Hita, C. Najera,
Tetrahedron: Asymmetry, 2006, 17, 729—733; (c) S. Guizzetti, M. Benaglia, L.
Raimondi, G. Celentano, Org. Lett., 2007, 9, 1247—1250; (d) S. F.Viózquez, A. B.
Caballero, G. Guillena, C. Nájera, E. G. Bengoa, Org. Biomol. Chem., 2012, 10,
4029—4035.
8
Prolinamide with βꢀamino alcohol: (a) M. R. Vishnumaya, S. K. Ginotra, V. K.
Singh, Org. Lett., 2006, 8, 4097—4099; (b) V. Maya, M. Raj, V. K. Singh, Org. Lett.,
2007, 9, 2593—2595; (c) Y. Okuyama, H. Nakano, Y. Watanabe, M. Makabe, M.
Takeshita, K. Uwai, C. Kabuto, E. Kwon, Tetrahedron Lett., 2009, 50, 193—197; (d)
R. M. Vishnumaya, V. K. Singh, J. Org. Chem., 2009, 74, 4289—4297; (e) X. H.
Chen, J. Yu, L. Z. Gong, Chem. Commun., 2010, 6437—6448.
Prolinamide of cholic acid methylester: G. L. Puleoa, A. Iuliano, Tetrahedron:
Asymmetry, 2007, 18, 2894—2900.
9
10 Aminoimidazole containing prolinamides: G. K. Tang, U. Gun, H. J. Altenbach,
Tetrahedron, 2012, 68, 10230—10235.
11 (L)ꢀProlinamides of chiral and achiral diamines: (a) S. Samanta, J. Liu, R. Dodda, C.
G. Zhao, Org. Lett., 2005, 7, 5321—5323; (b) R. Pedrosa, J. M. Andres, R. Manzano,
12

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DOI: 10.1039/C6RA23652A
P. Rodriguez, Eur. J. Org. Chem., 2010, 5310—5319; (c) J. P. Delaney, L. C.
Henderson, Adv. Synth. Catal., 2012, 354, 197—204.
12 Prolinamide of camphor: Z. H. Tzeng, H. Y. Chen, C. T. Huang, K. Chen,
Tetrahedron Lett., 2008, 49, 4134—4137.
13 Dipeptides and pseudopeptides: (a) M. Lei, L. X. Shi, G. Li, S. L. Chen, W. H. Fang,
Z. M. Ge, T. M. Cheng, R. T. Li, Tetrahedron 2007, 63, 7892—7898; (b) F. B. Chen,
S. Huang, H. Zhang, F. Y. Liu, Y. G. Peng, Tetrahedron, 2008, 64, 9585—9591; (c)
S. Chandrasekhar, K. Johny, C. R. Reddy, Tetrahedron: Asymmetry, 2009, 20,
1742—1745; (d) A. J. Pearson, S. Panda, Org. Lett. 2011, 13, 5548—5551; (e) J. G.
Hernandez, E. Juaristi, J. Org. Chem., 2011, 76, 1464—1467; (f) E. Machuca, Y.
Rojas, E. Juaristi, Asian J. Org. Chem. 2015, 4, 46—51; (g) I. Triandafillidi, A.
Bisticha, E. Voutyritsa, G. Galiatsatou, C. G. Kokotos, Tetrahedron, 2015, 71, 932—
940; (h) E. Machuca, E. Juaristi, Tetrahedron Lett. 2015, 56, 1144—1148.
14 Recent examples of aldol reactions catalyzed by prolinethioamides, see: (a) D. Gryko,
R. Lipinski, Adv. Synth. Catal., 2005, 347, 1948—1952; (b) D. Almasi, D. A. Alonso,
C. Najera, Adv. Synth. Catal. 2008, 350, 2467—2472; (c) D. Almasi, D. A. Alonso,
A. N. Balaguer, C. Najera, Adv. Synth. Catal. 2009, 351, 1123—1131; (d) B. Wang,
X. W. Liu, L. Y. Liu, W. X. Chang, J. Li, Eur. J. Org. Chem., 2010, 5951—5954; (e)
S. Fotaras, C. G. Kokotos, E. Tsandi, G. Kokotos, Eur. J. Org. Chem., 2011, 1310—
1317; (f) S. Fotaras, C. G. Kokotos, G. Kokotos, Org. Biomol. Chem. 2012, 10,
5613—5619; (g) P. Revelou, C. G. Kokotos, P. M. Minakakis, Tetrahedron 2012, 68,
8732—8738; (h) C. D. Maycock, M. R. Ventura, Tetrahedron: Asymmetry 2012, 23,
1262—1271; (i) C. G. Kokotos, J. Org. Chem., 2012, 77, 1131—1135.
15 Recent examples of aldol reactions catalyzed by sulfonamides, see: (a) K. Mei, S.
Zhang, S. He, P. Li, M. Jin, F. Xue, G. Luo, H. Zhang, L. Song, W. Duan, W. Wang,
Tetrahedron Lett., 2008, 49, 2681—2684; (b) E. Tsandi, C. G. Kokotos, S. Kousidou,
V. Ragoussis, G. Kokotos, Tetrahedron, 2009, 65, 1444—1449; (c) S. P. Zhang, X.
K. Fu, S. D. Fu, J. F. Pan, Catal. Commun. 2009, 10, 401—405; (d) S. J. Aratake, T.
Itoh, T. Okano, N. Nagae, T. Sumiya, M. Shoji, Y. Hayashi, Chem. Eur. J., 2007, 13,
10246—10256; (e) S. Gandhi, V. K. Singh, J. Org. Chem., 2008, 73, 9411—9416; (f)
H. Yang, S. Mahapatra, P. H. Cheong, R. G. Carter, J. Org. Chem., 2010, 75, 7279—
7290; (g) H. Yang, R. G. Carter, Org. Lett., 2008, 10, 4649—4652; (h) N. Hara, R.
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DOI: 10.1039/C6RA23652A
Tamura, Y. Funahashi, S. Nakamura, Org. Lett., 2011, 13, 1662—1665; (i) L. S. Zu,
H. X. Xie, H. Li, J. Wang, W. Wang, Org. Lett., 2008, 10, 1211—1214; (j) H. R.
Cabrera, G. Huelgas, J. M. H. Perez, P. J. Walsh, R. Somanathan, C. A. D. Parrodi,
Tetrahedron: Asymmetry, 2015, 26, 163—172; (k) J. R. Chen, H. H. Lu, X. Y. Li, L.
Cheng, J. Wan, W. Xiao, Org. Lett., 2005, 7, 4543—4545; (l) M. T. Robak, M. A.
Herbage, J. A. Ellman, Tetrahedron, 2011, 67, 4412—4416.
16 Chiral amines, see: (a) S. Z. Luo, H. Xu, J. Y. Li, L. Zhang, J. P. Cheng, J. Am. Chem.
Soc., 2007, 129, 3074–3075; (b) B. L. Zheng, Q. Z. Liu, C. S. Guo, X. L. Wang, L.
He, Org. Biomol. Chem. 2007, 5, 2913–2915; (c) S. Z. Luo, H. Xu, L. Zhang, J. Y. Li,
J. P. Cheng, Org. Lett., 2008, 10, 653–656; (d) X. H. Yu, W. Wang, Org. Biomol.
Chem., 2008, 6, 2037–2046; (e) L. Li, L. W. Xu, Y. D. Ju, G. Q. Lai, Synth.
Commun., 2009, 39, 764–774; (f) J. Y. Li, S. Z. Luo, J. P. Cheng, J. Org. Chem.,
2009, 74, 1747–1750; (g) C. S. Da, L. P. Che, Q. P. Guo, F. C. Wu, X. Ma, Y. N. Jia,
J. Org. Chem., 2009, 74, 2541–2546; (h) S. Z. Luo, J. Y. Li, L. Zhang, H. Xu, J. P.
Cheng, Chem. Eur. J. 2008, 14, 1273–1281; (i) J. Agarwal, R. K. Peddinti, J.
Org.Chem., 2011, 76, 3502–3505; (j) B. Xu, L. Li, S. Gou, Tetrahedron: Asymmetry,
2013, 24, 1556–1561; (k) JꢀH. Lin, CꢀP. Zhang, JꢀC. Xiao, Green Chem. 2009, 11,
1750–1753.
17 Organic salts: (a) M. Lombardo, S. Easwar, F. Pasi, C. Trombini, Adv. Synth. Catal.,
2009, 351, 276–282; (b) V. Bisai, V. K. Singh, Synlett, 2009, 933–936; (c) A.
Karmakar, T. Maji, S. Wittmann, O. Reiser, Chem. Eur. J., 2011, 17, 11024–11029;
(d) T. Ichibakase, M. Nakajima, Org. Lett., 2011, 13, 1579–1581; (e) E. Montroni, M.
Lombardo, A. Quintavalla, C. Trombini, M. Gruttadauria, F. Giacalone, Chem. Cat.
Chem., 2012, 4, 1000–1006; (f) E. G. Doyaguez, A. F. Mayoralas, Tetrahedron 2012,
68, 7345–7354; (g) L. A. A. Momani, A. Lataifeh, Inorg. Chim. Acta, 2013, 394,
176–183
.
18 Recyclable proline based organocatalysts: (a) W. Miaoa, T. H. Chan, Adv. Synth.
Catal. 2006, 348, 1711–1718; (b) Y. Wu, Y. Zhang, M. Yu, G. Zhao, S. Wang, Org.
Lett. 2006, 8, 4417–4420; (c) D. Front, C. Jimeno, M. A. Pericas, Org. Lett., 2006, 8,
4653–4655; (d) Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M.
Shoji, Angew. Chem. Int. Ed., 2006, 45, 958–961; (e) F. Giacalone, M. Gruttadauria,
A. M. Marculescu, R. Noto, Tetrahedron Lett., 2007, 48, 255–259; (f) S. Luo, X. Mi,
L. Zhang, S. Liu, H. Xu, J. P. Cheng, Tetrahedron 2007, 63, 1923–1930; (g) G.
Guillena, M. C. Hita, C. Najera, S. F. Viozquez, J. Org. Chem., 2008, 73, 5933–5943;
(h) J. Gao, J. Liu, D. Jiang, B. Xiao, Q. Yang, J. Mol. Catal. A: Chem., 2009, 313,
79–87; (i) Y. Yang, Y. H. He, Z. Guan, W. D. Huang, Adv. Synth. Catal., 2010, 352,
2579–2587; (j) S. S. Khan, J. Shah, J. Liebscher, Tetrahedron 2010, 66, 5082–5088;
(k) T. Miura, K. Imai, M. Ina, N. Tada, N. Imai, A. Itoh, Org. Lett. 2010, 12, 1620–
1623; (l) C. L. Wu, X. K. Fu, S. Li, Tetrahedron 2011, 67, 4283–4290; (m) T. Miura,
K. Imai, H. Kasuga, M. Ina, N. Tada, N. Imai, A. Itoh, Tetrahedron 2011, 67, 6340–
6346; (n) A. M. Castaneda, B. Poladura, H. R. guezꢀSolla, C. Concellon, V. Amo,
14

Page 15 of 15
RSC Advances
View Article Online
DOI: 10.1039/C6RA23652A
Org. Lett., 2011, 13, 3032–3035; (o) J. G. Hernandez, E. Juaristi, Tetrahedron 2011,
67, 6953–6959; (p) V. Gauchot, A. R. Schmitzer, J. Org. Chem., 2012, 77, 4917–
4923; (q) X. Zhang, W. Zhao, C. Qu, L. Yang, Y. Cui, Tetrahedron: Asymmetry,
2012, 23, 468–473; (r) H. L. Yang, S. W. Li, X. Y. Wang, F. W. Zhang, X. Zhong, Z.
P. Dong, J. T. Ma, J. Mol. Catal. A: Chem., 2012, 363–364, 404–410; (s) J. G.
Hernandez, V. GarciaꢀLopez, E. Juaristi, Tetrahedron, 2012, 68, 92–97; (t) A. B.
Caballero, G. Guillena, C. Nájera, E. Faggi, R. M. Sebástian, A. Vallribera,
Tetrahedron, 2013, 69, 1307–1315; (u) C. Qu, W. Zhao, L. Zhang, Y. Cui, Chirality,
2014, 26, 209–213; (v) D. E. Siyutkin, A. S. Kucherenko, S. G. Zlotin, Tetrahedron
2010, 66, 513–518; (w) A. BañónꢀCaballero, G. Guillena, C. Nàjera, Green Chem.
2010, 12, 1599–1606; (x) A. MongeꢀMarcet, X. Cattoën, D. A. Alonso, C. Nàjera, M.
W. C. Man, R. Pleixats, Green Chem. 2012, 14, 1601–1610. (y) P. Llanes, S.
Sayalero, C RodriguezꢀEscrich, M. A. Pericàs, Green Chem. 2016, 18, 3507–3512.
19 (a) G. D. Yadav, S. Singh, Tetrahedron: Asymmetry, 2015, 26, 1156–1166; (b) M. S.
Chauhan, P. Kumar, S. Singh, RSC Adv., 2015, 5, 52636–52641; (c) G. D. Yadav, S.
Singh, Tetrahedron: Asymmetry, 2016, 27, 123–129; (d) G. D. Yadav, S. Singh,
Tetrahedron: Asymmetry, 2016, 27, 463–466.
20 Z. Zhang, H. Y. Bae, J. Guin, C. Rabalakos, M. V. Gemmeren, M. Leutzsch, M.
Klussmann, B. List, Nature communication, 2016, 7, 12478.
15