Recyclable siloxy serine organocatalyst for the direct asymmetric mannich reactions in ionic liquids

Article abstract of DOI:10.1080/00397911.2010.481750

A recyclable siloxy-L-serine organocatalyst has been developed to catalyze the asymmetric direct three-component Mannich reactions in ionic liquid hmim[PF₆], furnishing the β-amino carbonyl scaffold in high enantio- and diastereoselectivities.

Full text of DOI:10.1080/00397911.2010.481750

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Recyclable Siloxy Serine Organocatalyst
for the Direct Asymmetric Mannich
Reactions in Ionic Liquids
Fui-Fong Yong a & Yong-Chua Teo a
a Natural Sciences and Science Education, National Institute of
Education, Nanyang Technological University, Singapore
Published online: 30 Mar 2011.
To cite this article: Fui-Fong Yong & Yong-Chua Teo (2011): Recyclable Siloxy Serine Organocatalyst
for the Direct Asymmetric Mannich Reactions in Ionic Liquids, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:9, 1293-1300
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Synthetic Communications1, 41: 1293–1300, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.481750
RECYCLABLE SILOXY SERINE ORGANOCATALYST
FOR THE DIRECT ASYMMETRIC MANNICH REACTIONS
IN IONIC LIQUIDS
Fui-Fong Yong and Yong-Chua Teo
Natural Sciences and Science Education, National Institute of Education,
Nanyang Technological University, Singapore
GRAPHICAL ABSTRACT
Abstract A recyclable siloxy-L-serine organocatalyst has been developed to catalyze the
asymmetric direct three-component Mannich reactions in ionic liquid hmim[PF6], furnish-
ing the b-amino carbonyl scaffold in high enantio- and diastereoselectivities. The direct
Mannich reaction between a selection of aromatic aldehydes and ketones resulted in good
yields and high enantioselectivities.
Keywords b-Amino carbonyl compounds; asymmetric Mannich; enantiomeric excess;
organocatalyst; serine
INTRODUCTION
The direct catalytic asymmetric Mannich reaction[1] is one of the most effective
carbon–carbon bond-forming reactions used for synthesizing enantiomerically
enriched nitrogenous molecules including amino acids, amino alcohols, and their
derivatives. The potential of this multicomponent reaction to generate diversity
and the construction of these optically active b-amino carbonyl units as useful chiral
building blocks for numerous biologically active and medicinal agents have attracted
attention from synthetic chemists and the pharmaceutical industry.[2]
List et al. reported the first direct organocatalytic asymmetric three-component
Mannich reaction of an aldehyde, 4-methoxyaniline (p-anisidine), and a ketone
catalyzed by proline.[3] Catalytic indirect and direct asymmetric Mannich
reactions were further broadened by the research groups of Barbas, Cordova, and
Jacobsen.[4]
Received November 3, 2009.
Address correspondence to Yong-Chua Teo, Natural Sciences and Science Education, National
Institute of Education, Nanyang Technological University, Singapore. E-mail: yongchua.teo@nie.edu.sg
1293

1294
F.-F. YONG AND Y.-C. TEO
The recent strategies for the reuse of organocatalysts in ionic liquids have been
mainly concerned with the chemical functionalization of the ionic liquid with the
purpose of attaching the chiral organocatalyst. In most cases, proline was introduced
to the sidechains of the ionic liquid.[5] This strategy ensures the recyclability of the
catalysts, but it can be time-consuming, resulting in uneconomical transformations
and associated problems with manipulation of ionic liquids in multistep syntheses.
Herein, we report an efficient and highly enantioselective recyclable three-
component Mannich reaction catalyzed by an acyclic silyl-protected serine-derived
organocatalyst in the presence of the ionic liquid, hmim[PF6]. It is worth noting that
prior chemical attachment of the ionic liquid to the siloxy serine catalyst was not
necessary for enabling recyclability.
Recently, our group has reported an efficient protocol for the direct asymmetric
three-component Mannich reaction in water catalyzed by a siloxy serine organo-
catalyst.[6] This method has proven to be practical and environmentally friendly
because it excluded the use of organic solvents and toxic metals. Based on this
precedent, we envision that the direct Mannich reaction can also be performed as a
three-component reaction in ionic liquid with the intent of recovering and reusing
the organocatalyst for further reaction. This would thus greatly enhance the atom
economy of the process.
RESULTS AND DISCUSSION
Inaninitialstudy,thethree-componentMannichreactionbetweencyclohexanone,
4-nitrobenzaldehyde, and p-anisidine catalyzed by tert-butyl-diphenyl-silanyl (TBDPS)-
L-serine organocatalyst in the presence of bmim[BF4] and hmim[PF6] were initiated. The
use of ionic liquid hmim[PF6] as solvent afforded the product in an excellent yield of 91%
and good enantioselectivity of 84% (syn=anti, 89:11), while ionic liquid bmim[BF4]
afforded moderate yield of 82% and enantioselectivity of 70% (syn=anti, 80:20).
The optimized condition was extended to a series of aldehyde acceptors and
ketone donors to explore the generality of this catalytic system, and the results are
summarized in Table 1. In most cases, the Mannich products were obtained in good
yields and high enantioselectivities. In the case of cyclohexanone as the cyclic ketone
donor, the reactive aldehydes underwent the catalytic process to afford the products
in syn selectivity with both good yields and enantioselectivities (Table 1, entries 1
and 2). The use of 4-nitrobenzaldehyde afforded an excellent yield of 91% and good
enantioselectivity of 84% compared to 4-bromobenzaldehyde, which afforded a
moderate yield of 50% and relatively high enantioselectivity of 71%.
To broaden the scope of this transformation, a number of aromatic aldehydes
were reacted with the acyclic O-benzyl hydroxyacetone under these conditions to
afford the 1,2-protected amino alcohols. In all cases, the reaction proceeded regiose-
lectively with the carbon–carbon bond occurring at the methylene carbon. Interest-
ingly, the reactions afforded anti selectivity, and the corresponding 1,2-protected
amino alcohols were obtained in excellent enantioselectivities and good yields (entries
3–8). Aromatic nitrobenzaldehyde with para- (p), meta- (m), and ortho- (o) positions
showed comparable yields and enantioselectivities (entries 3–5). The reaction of
4-cyanobenzaldehyde with the O-benzyl hydroxyacetone under the influence of the
catalyst afforded the product in good yield (64%) and excellent enantioselectivity

RECYCLABLE SILOXY SERINE ORGANOCATALYST
1295
Table 1. Direct asymmetric Mannich reactions catalyzed by the siloxy serine organocatalyst in
hmim[PF6]a
Entry
1
R1
Product
Yield (%)b
Syn=antic
Ee (%)d
84
4-NO2C6H4
91
89:11
2
3
4
5
4-BrC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
50
52
70
66
75:25
18:82
17:83
6:94
71
78
80
82
6e
4-BrC6H4
66
30:70
62
7
4-CNC6H4
2-Naphthyl
64
89
15:85
40:60
91
55
8e
aUnless otherwise noted, the reaction was performed with aldehyde (0.5 mmol), ketone (cyclohexanone:
1.5 mmol, O-benzyl hydroxyacetone: 1.35 mmol), p-anisidine (0.45 mmol), and catalyst (0.045 mmol) in
hmim[PF6] (0.5 mL) at room temperature for 14 h.
bCombined yield of isolated diastereomers.
cDiastereoselectivity was determined by 1H NMR analysis of the reaction mixture.
dEnantiomeric excess refers to the major isomer and was determined by HPLC analysis on a chiral
phase.
eThe reaction was performed for 38 h.

1296
F.-F. YONG AND Y.-C. TEO
Table 2. Recyclability studies of the siloxy serine organocatalyst–catalyzed direct Mannich reaction in
hmim[PF6]a
Cycle
Time (h)
Yield (%)b
Anti=syn (%)c
Ee (%)d
1
2
3
4
5
14
24
24
36
42
91
85
47
32
31
89:11
84:16
84:16
70:30
68:32
84
84
84
68
65
aUnless otherwise noted, the reaction was performed with 4-nitrobenzaldehyde (0.5 mmol), cyclohexa-
none (1.5 mmol), p-anisidine (0.45 mmol), and catalyst (0.045 mmol) in hmim[PF6] (0.5 mL) at room
temperature.
bCombined yield of isolated diastereomers.
cDiastereoselectivity was determined by 1H NMR analysis of the reaction mixture.
dEnantiomeric excess refers to the syn isomer and was determined by HPLC analysis on a chiral phase.
(91%, entry 7). Moreover, the use of a neutral aldehyde, 2-naphthaldehyde, also
afforded the product in excellent yield and moderate enantioselectivity (entry 8).
Next, we continued our study by exploring the recyclability of the siloxy serine
organocatalyst. The reaction of 4-nitrobenzaldehyde (0.5 mmol), cyclohexanone
(1.5 mmol), and p-ansidine (0.45 mmol) in hmim[PF6] (0.5 ml) was selected in this
model study. It was demonstrated that identical reactivities and stereoselectivities
were observed using this recycled ionic liquid residue for up to three cycles and
the biphasic property of the ionic liquid was maintained. However, some loss of
reactivity and enantiocontrol of this system was observed in the fourth cycle. The
results of the recyclability study are shown in Table 2.
EXPERIMENTAL
Chemicals and solvents were either purchased from commercial suppliers or
purified by standard techniques. Analytical thin-layer chromatography (TLC) was
performed using Merck 60 F254 precoated silica-gel plates (0.2 mm thick). Sub-
sequent to elution, plates were visualized using UV radiation (254 nm) on Spectroline
model ENF-24061=F 254 nm. Flash chromatography was performed using Merck
silica gel 60 with analytical-reagent (AR)–grade solvents. Proton nuclear magnetic
resonance spectra (1H NMR) were recorded on a Bruker Avance DPX 400 spectro-
1
photometer (CDCl3 as solvent). Chemical shifts for H NMR spectra are reported
as d in units of parts per million (ppm) downfield from SiMe4 (d 0.0) and relative
to the signal of chloroform-d (d 7.2600, singlet). Carbon nuclear magnetic resonance
spectra (13C NMR) are reported as d in units of parts per million (ppm) downfield
from SiMe4 (d 0.0) and relative to the signal of chloroform-d (d 77.03, triplet).
High-performance liquid chromatography (HPLC) was carried out using an Agilent
110 series LC–G1311A QUAT pump, G1315B DAD detector, and integrator. All
Mannich reactions were carried out under an atmosphere of air in a closed system.
Organic substrates cyclohexanone, p-anisidine, 4-nitrobenzaldehyde, 3-nitro-
benzaldehyde, 2-nitrobenzaldehyde, 4-cyanobenzaldehyde, 4-bromobenzaldehyde,
2-naphthaldehyde, ethyl glyoxylate, 1-butyl-3-methylimidazolium tetrafluoroborate
([bmim][BF4]), 1-butyl-3-methylimidazolium hexafluorophosphate ([hmim][PF6]),

RECYCLABLE SILOXY SERINE ORGANOCATALYST
1297
tert-butyldiphenylchlorosilane, and Z-Ser-OH were all commercially available and
were used without any purification. O-Benzyl hydroxyacetone was purified by stan-
dard methods prior to use.
General Procedure for the Synthesis of (2S)-2-
Benzyloxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-
propionic Acid
Imidazole (3.8 g, 55.8 mmol, 2.6 equiv) and TBDPSCl (6.0 mL, 23 mmol, 1.1
equiv) were added at 0 ꢀC to a dimethylformamide (DMF) solution (50 mL) of
(2S)-2-benzyloxycarbonylamino-3-hydroxy-propionic acid (5.0 g, 20.9 mmol). The
reaction was stirred for 18 h at room temperature and quenched by the addition
of water and ether. The aqueous phase was extracted with ether (3 ꢁ 100 mL). The
combined organic extracts were dried with anhydrous MgSO4, and the solvent
was removed under reduced pressure. The crude siloxy ether product was purified
by silica-gel column chromatography (hexane–ethyl acetate 2:1) to afford a white
solid (7.3 g, 73%).
Pd=C (4.89 g, 10 wt%, 4.6 mmol, 0.3 equiv) was added at room temperature to
a methanol solution (100 mL) of (2S)-2-benzyloxycarbonylamino-3-(tert-butyl-
diphenyl-silanyl oxy)-propionic acid (7.3 g, 15.3 mmol). The reaction mixture was
stirred for 6 h at that temperature under a hydrogen atmosphere in a closed system.
The filtration of the inorganic materials through celite and removal of methanol
under reduced pressure afforded the crude product. Purification by silica-gel
chromatography (dichloromethane=methanol 9:1) afforded the catalyst as a white
1
solid (4.1 g, 79%). H NMR (300 MHz, DMSO-d6): d (ppm) 0.98 (s, 9H), 3.35 (dd,
J ¼ 7.6, 3.2 Hz, 1H), 3.82 (dd, J ¼ 10.8, 7.6 Hz, 1H), 3.92 (dd, J ¼ 10.4, 3.2 Hz, 1H),
7.40–7.47 (m, 6H), 7.65–7.68 (m, 4H); 13C NMR (100 MHz, DMSO-d6): d (ppm)
19.3, 27.1, 56.7, 64.4, 128.2, 128.3, 130.2, 130.3, 133.1, 133.3, 135.7, 135.8, 168.3
Representative Procedure for Asymmetric Direct Mannich Reaction:
Preparation of (2S,1’S)-2-[(4-Methoxy-Phenylamino)-(4-nitro-
Phenyl)-methyl]-cyclohexanone 1a
A catalytic amount of siloxyserine (7.75 mg, 0.0225 mmol, 0.05 equiv) was added
to a vial containing 4-nitrobenzaldehyde (0.0760 g, 0.5 mmol, 1.1 equiv), p-anisidine
(0.055 g, 0.45 mmol, 1.0 equiv), cyclohexanone (0.26 mL, 2.5 mmol, 5.0 equiv), and

1298
F.-F. YONG AND Y.-C. TEO
1-butyl-3-methylimidazolium hexafluorophosphate ([hmim][PF6]) (0.5 mL) under air
in a closed system. The reaction mixture was stirred at room temperature for 14 h.
The reaction vial was extracted with diethyl ether (5 ꢁ 5 ml). The solvent in the
combined organic extracts was removed under reduced pressure. The crude Mannich
product was purified by silica-gel column chromatography (hexane=ethyl acetate 4:1)
to afford 1a as a yellow liquid (0.1450 g, 91% yield).
Representative Data of (2S,1’S)-2-[(4-Methoxy-phenylamino)-
(4-nitro-phenyl)-methyl]-cyclohexanone 1a
1
Brown oil (145 mg, 91%); H NMR (400 MHz, CDCl3): d (ppm) 1.60–2.15
(m, 4H), 2.03–2.06 (m, 2H), 2.30–2.46 (m, 2H), 2.79–2.84 (m, 1H), 3.67 (s, 3H),
4.34 (br s, 1H), 4.79 (d, J ¼ 4.1 Hz, 1H), 6.46 (d, J ¼ 8.7 Hz, 2H), 6.66 (d, J ¼ 8.7 Hz,
2H), 7.54 (d, J ¼ 8.7 Hz, 2H), 8.212 (d, J ¼ 8.7 Hz, 2H) ppm; 13C NMR (100 MHz,
CDCl3): d 24.8, 27.0, 28.9, 42.6, 55.5, 56.3, 57.9, 114.7, 115.5, 123.6, 128.5, 140.7,
147.0, 149.8, 152.6, 210.6 ppm.
1
The diastereomeric anti=syn ratio was determined by H NMR analysis of the
reaction mixture: d (ppm) 4.79 (d, 1H, J ¼ 4.1 Hz, syn, major), d 4.64 (d, 1H, J ¼
8.2 Hz, anti, minor). Enantiomeric excess was determined by HPLC with a Chiralcel
AD-H (hexane=i-PrOH ¼ 85=15, 0.5 mL=min, k ¼ 254 nm, 20 ꢀC): tR ¼ 71.7 min
(minor) and 75.4 min (major). The absolute of configuration of 1a was extrapolated
by comparison of the HPLC data with the literature data.[1g,4f]
HPLC Data for Mannich Products 1b–1i
(2R,1’S)-2-[(4-Bromo-phenyl)-(4-methoxy-phenylamino)-methyl]-cyclo-
hexanone 1b. Enantiomeric excess was determined by HPLC with a Chiralcel
AS-H (hexane=i-PrOH ¼ 90=10, 0.5 mL=min, k ¼ 254 nm, 20 ꢀC): tR ¼ 61.7 min
(major) and 56.6 min (minor).
(3R,4R)-4-(4-Methoxyphenylamino)-3-benzyloxy-4-(4-nitrophenyl)butan-
2-one 1c. Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
(hexane=i-PrOH ¼ 85=15, 1 mL=min, k ¼ 280 nm, 20 ꢀC): tR ¼ 22.0 min (minor) and
27.2 min (major).
(3R,4R)-4-(4-Methoxyphenylamino)-3-benzyloxy-4-(3-nitrophenyl)butan-
2-one 1d. Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
(hexane=i-PrOH ¼ 90=10, 1 mL=min, k ¼ 280 nm, 20 ꢀC): tR ¼ 19.1 min (minor) and
25.1 min (major).
(3R,4R)-4-(4-Methoxyphenylamino)-3-benzyloxy-4-(2-nitrophenyl)butan-
2-one 1e. Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
(Hexane=i-PrOH ¼ 90=10, 1 mL=min, k ¼ 254 nm, 20 ꢀC): tR ¼ 15.4 min (minor) and
26.1 min (major).
(3R,4R)-4-(4-Methoxyphenylamino)-3-benzyloxy-4-(4-bromophenyl)-
butan-2-one 1f. Enantiomeric excess was determined by HPLC with a Chiralcel
AD-H (hexane=i-PrOH ¼ 90=10, 1 mL=min, k ¼ 254 nm, 20 ꢀC): tR ¼ 12.6 min
(minor) and 19.6 min (major).

RECYCLABLE SILOXY SERINE ORGANOCATALYST
1299
(3R,4R)-4-(4-Methoxyphenylamino)-3-benzyloxy-4-(4-cyanophenyl)butan-
2-one 1g. Enantiomeric excess was determined by HPLC with a Chiralcel AS-H
(hexane=i-PrOH ¼ 90=10, 1 mL=min, k ¼ 254 nm, 20 ꢀC): tR ¼ 28.7 min (minor) and
35.1 min (major).
(3R,4R)-4-(4-Methoxyphenylamino)-3-benzyloxy-4-(naphthalen-2-yl)-
butan-2-one 1h. Enantiomeric excess was determined by HPLC with a Chiralcel
ODH (hexane=i-PrOH ¼ 90=10, 0.5 mL=min k ¼ 254 nm, 20 ꢀC): tR ¼ 43.1 min
(minor) and 34.9 min (major).
CONCLUSION
In summary, we have demonstrated an efficient one-pot direct Mannich reac-
tion catalyzed by a recyclable siloxy-L-serine organocatalyst in hmim[PF6] without
prior chemical functionalization. Important features of this new transformation
include the following: (1) the direct Mannich reaction proceeded in the presence of
ionic liquid using simple procedures; (2) prior chemical attachment of the siloxy
serine organocatalyst activity was not necessary for recyclability; (3) the siloxy serine
catalyst can be prepared easily and economically from commercially available
sources, with both enantiomers readily available; and (4) the siloxy serine organoca-
talyst in hmim[PF6] can be recycled up to three times with comparable enantioselec-
tivities. Further research on broadening the scope of this siloxy serine organocatalyst
to other asymmetric reactions is currently under investigation.
ACKNOWLEDGMENT
We thank the National Institute of Education (RP05=06 TYC), Nanyang
Technological University, for their generous financial support.
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