β-cyclodextrin-mediated acetic acid catalyzed diastereoselective Mannich reaction in water

Article abstract of DOI:10.1055/S-0032-1317156

A highly efficient diastereoselective Mannich reaction has been carried out in water using a catalytic amount of β-cyclodextrin as a chiral host in the presence of acetic acid to give the corresponding β-aminoketones (Mannich bases) with good yield (up to 98%) and excellent diastereomeric excess (up to >99%). This Brensted acid-chiral cyclodextrin composite catalyzed reaction proceeds in a syn-selective manner with 98:2 syn/anti selectivity when propiophenone is used as the ketone moiety and in an antiselective manner with 100:0 (antilsyn) selectivity when cyclohexanone is used. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0032-1317156

2328▌
LETTER
letter
β-Cyclodextrin-Mediated Acetic Acid Catalyzed Diastereoselective Mannich
Reaction in Water
Diastereoselective Mannich Reaction in Water
Subbiah Sukumari, Ismail Abulkalam Azath, Kasi Pitchumani*
School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
Fax +91(452)2459181; E-mail: pit12399@yahoo.com
Received: 16.06.2012; Accepted after revision: 30.07.2012
from poor diastereoselectivity too.11–14 Vencato et al.15 re-
Abstract: A highly efficient diastereoselective Mannich reaction
ported the crystal structure of the syn-isomer of the
has been carried out in water using a catalytic amount of β-cyclo-
Mannich product which was isolated by the condensation
of para-chloro benzylidene aniline and the trimethylsilyl
dextrin as a chiral host in the presence of acetic acid to give the cor-
responding β-aminoketones (Mannich bases) with good yield (up to
98%) and excellent diastereomeric excess (up to >99%). This enol ether of propiophenone. Though the Mannich reac-
Brønsted acid–chiral cyclodextrin composite catalyzed reaction
proceeds in a syn-selective manner with 98:2 syn/anti selectivity
when propiophenone is used as the ketone moiety and in an anti-
the yield and diastereomeric ratio obtained for halogen-
selective manner with 100:0 (anti/syn) selectivity when cyclohexa-
none is used.
tion of cyclohexanone with aromatic amines and aromatic
aldehydes catalyzed by Brønsted acids is well established,
substituted anilines were lower than those for the remain-
ing anilines.16–20
Key words: mannich bases, diastereoselectivity, cyclodextrins,
There has been an increasing interest in the development
of clean technologies to replace hazardous organic sol-
vents with relatively environmentally benign ones and
therefore organic reactions in aqueous media have attract-
ed much attention. However, a major disadvantage of wa-
ter as a solvent is that most organic compounds are
insoluble and that, as a result, the reactions are slower.
However, they can be made more practicable if they are
performed with supramolecular water-soluble hosts.21
aqueous medium, supramolecular chemistry
Chiral nitrogen-containing molecules are ubiquitous in
nature and form important structural motifs in both natural
and synthetic biologically active molecules.1 The catalytic
asymmetric Mannich reaction is one of the most powerful
methods for the construction of chiral nitrogen-containing
molecules.2 This type of conversion is recognized as a vi-
able approach to prepare the same products in enantio-
and diastereomerically pure forms via asymmetric or-
ganocatalysis,3 by (i) chiral amines (such as L-proline),
(ii) chiral Brønsted bases (such as cinchona alkaloids
bearing thiourea moieties), and (iii) chiral Brønsted acids
(such as phosphoric acids).4
Among the various supramolecular hosts, cyclodextrins
have generated enormous interest as enzyme models. Cy-
clodextrins (CDs) are cyclic oligosaccharides possessing
hydrophobic cavities and they mimic enzymes in their ca-
pability to bind substrates selectively and catalyze chemi-
cal reactions with high selectivity. Cyclodextrins have
been studied extensively as biomimetic catalysts.22 The
catalytic reactions of CDs involve reversible formation of
host-guest complexes with substrates through non-cova-
lent bonding. The complex formation with CD can alter
product distribution in organic reactions. These character-
istics arise from the geometrical constraints of the guest
molecules upon inclusion into CD cavity. Apart from this,
with the CD cavity being chiral, it can also induce asym-
metry in organic reactions.23 In CD-catalyzed asymmetric
reactions, the following criteria are required for efficient
chiral induction: a phenyl ring in the substrate to form a
stronger, more tight CD inclusion complex and suitably
positioned functional groups to interact with CD hydroxyl
groups to ensure chiral recognition.24 These attractive fea-
tures of CDs prompted us to use CD as a chiral promoter
in water for the asymmetric Mannich reaction.
Though Mannich reaction has been studied in detail, only
few reports are available for diastereoselective Mannich
reaction involving only aromatic substrates. Kobayashi et
al. studied the diastereoselective Mannich reaction of all
the three aromatic compounds either indirectly or directly
by using Lewis acid catalysts5–7 and Brønsted acid–
surfactant–combined catalyst (BASC) in water.8,9 A dia-
stereomeric ratio of 4:1 was reported, when they carried
out the Mannich reaction of the aldimine of benzaldehyde
and aromatic amines with the silyl enol ether of propio-
phenone using Yb(OTf)3 at –45 °C.7 Loh et al. studied the
diastereoselective Mannich reaction of aromatic alde-
hydes, aromatic amines and the silyl enol ethers of propi-
ophenone using InCl3 in pure water and a diastereomeric
ratio of about 60:40 was observed; they also identified the
syn-isomer as the major isomer using the chemical shifts
of the 1H NMR spectrum.10 Other studies on asymmetric
Mannich reactions involving aromatic substrates suffered
Our interest in using cyclodextrins (CDs) as catalysts in
organic reactions25 and in promoting chiral induction26
has prompted us to study the effect of β-CD on the one-pot
three-component Mannich reaction. Since β-CD can ef-
fectively encapsulate an aromatic ring, substrates possess-
ing an aryl ring were used in the present study. Initial
SYNLETT 2012, 23, 2328–2332
Advanced online publication: 10.09.2012
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DOI: 10.1055/s-0032-1317156; Art ID: ST-2012-B0519-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereoselective Mannich Reaction in Water
2329
investigation of the Mannich reaction of benzaldehyde, trin–substrate complexation can occur in polar nonaque-
para-chloroaniline and acetophenone with acetic acid– ous solvents through lyophobic binding of substrates.27
water (1:1) mixtures gave 83% yield with only 2% enan- The lyophobic force involved should be similar to that in
tiomeric excess in the presence of β-CD even at –10 °C. aqueous solution; the energy of the system is lowered by
With the aim of enhancing the diastereoselectivity, we ex- increased solvent–solvent interaction when the solvent–
amined the reaction using propiophenone instead of ace- substrate and solvent–cavity interfaces are diminished.
tophenone. In the absence of β-CD, the ratio of syn to anti The observation of diastereomeric excesses in DMSO
was found to be 52:48 (Table 1, entry 2). Interestingly may be due to the lyophobic forces. Though we got good
when the reaction was carried out in the presence of β-CD, diastereomeric excesses in DMSO, the yield was much
the Mannich products were formed with excellent syn lower at –10 °C. However, at 10 °C, poor diastereomeric
selectivity (diastereomeric ratio of 98:2 syn/anti, Table 1, excess and moderate yields were obtained in DMSO, sim-
entry 3), but with no appreciable enhancement of the en- ilar to that obtained in the case of Mannich reaction car-
antiomeric excess. The ratio of syn/anti was determined ried out without β-CD. These results indicate that though
by HPLC on a chiral stationary phase (Figure 1).
water is so far the best solvent for CD-binding and subse-
quent catalytic processes, it is still possible to realize in-
clusion complex formation in DMSO medium.
The influence of other experimental parameters such as
the amount of β-CD, reaction time and amount of acetic
acid were also optimized. With a shorter reaction time
(12–24 h), only low to moderate yields were observed
(Table 1, entries 10 and 11). Increasing the time to beyond
Table 1 Optimization of Reaction Conditionsa
Entry
CD
Solvent
Yieldb (%) drc (syn:anti)
Figure 1 HPLC trace of 3-(4-chlorophenylamino)-2-methyl-1,3-
diphenylpropan-1-one in the (a) absence of β-CD and (b) presence of
β-CD.
1
2
–
H2O
Nil
67
–
–
MeCN
H2O
52:48 (4a′)
98:2
98:2
–
3
β-CD
γ-CD
PABCD
PABCD
β-CD
β-CD
β-CD
β-CD
β-CD
β-CD
β-CD
β-CD
β-CD
73
The major product (98%) was identified as syn, by com-
paring the 13C NMR spectrum of this product with a liter-
ature report.10 The signal for the C2-methine at δ = 11.39
ppm corresponded to the syn- isomer (major) and the sig-
nal at δ = 16.67 ppm corresponded to the anti-isomer (mi-
nor). The presence of the signal at δ = 11.24 ppm and the
absence of the signal at δ = 16.67 ppm in the 13C NMR
spectrum of our product (4a) confirmed predominant for-
mation of the syn-isomer (Figure S6).
4
H2O
73
5
DMSO
H2O
Nil
Nil
41
6
–
7
MeCN
DMSO
DMSO
H2O
52:48
65:35
95:5
–
8
53
9
39d
Nile
24f
73g
43h
<10i
Nilj
In order to find out the effect of CD cavity size on the
diastereomeric ratio, the reaction was carried out with γ-
CD and similar results as those for β-CD were obtained
(Table 1, entry 4). As chemical modification of cyclodex-
trins is expected to improve the enantioselectivity in
asymmetric catalysis, the reaction was also carried out in
per-6-amino β-cyclodextrin (per-6-ABCD) and no reac-
tion was observed in DMSO and in water (Table 1, entries
5 and 6). Consequently, β-CD was used for further studies
due to its low cost and easy availability. When the reac-
tion was carried out in organic solvents such as acetoni-
trile and DMSO, the diastereomeric ratio obtained was
poor (Table 1, entries 7 and 8). However in DMSO, at –10 °C,
the diastereomeric ratio was improved to 95:5, but with
lower yield (Table 1, entry 9). Although the binding of
substrates by β-cyclodextrin in polar nonaqueous solvents
such as DMSO is not as strong as in water, the formation
of inclusion complexes of guest molecules with CD
through H-bonding or ion pairing or lyophobic forces is
still possible. Breslow and Siegel reported that cyclodex-
10
11
12
13
14
15
H2O
98:2
98:2
98:2
98:2
–
H2O
H2O
H2O
H2O
a Reaction conditions: aniline (1 mmol), benzaldehyde (1 mmol), pro-
piophenone (1 mmol), CD (0.1 mmol) in AcOH–H2O (1:1) at 10 °C
for 48 h.
b Isolated yield.
c Analyzed by HPLC.
d The reaction was performed at –10 °C.
e The reaction was carried out for 12 h.
f The reaction was carried out for 24 h.
g The reaction was carried out for 60 h.
h Amount of CD used was 1 mmol.
i Amount of CD used was 2 mmol.
j Amount of CD used was 5 mmol.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2328–2332

2330
S. Sukumari et al.
LETTER
48 hours did not improve the yield (Table 1, entry 12). Op- mation of the Mannich product is the reversible condensa-
timization of the reaction conditions with different equiv- tion between amines and carbonyl compounds to form
alents of CD, showed that higher CD equivalents (>0.1 imines. To drive the reaction towards the product side, the
equiv) gave a lower yield without any change in diastereo- by-product (H2O) generated needs to be removed. This
meric ratio and enantiomeric excess (Table 1, entries 13– can be achieved by transforming the imines into iminium
15). This may be attributed to the inclusion of all three ions in the presence of catalytic amounts of an acid.29 The
substrates in three different CD cavities. It is relevant to resultant iminium ion is readily attacked by the nucleo-
mention that a catalytic amount of CD (0.1 equivalent) phile. The formation of iminium ion is less favored in the
was sufficient to get an excellent diastereomeric ratio case of amines with electron-releasing substituents and al-
(98:2). Since CDs are unstable in acid medium with a pH dehydes with electron-withdrawing substituents as they
value lower than 2, the pH of the reaction was measured destabilize the iminium ion. Similarly, electron-with-
during the course of reaction. It was found to be about 3, drawing substituents on the amines and electron-releasing
indicating the stability of CD under our experimental con- substituents on the aldehydes do not favor the formation
ditions. These preliminary results reveal that 0.1 equiva- of imines. Consequently, Mannich reactions of only mod-
lent of β-CD acts as an excellent chiral inductor with erately activated susbtrates bearing substituents like Cl or
optimum conditions such as the presence of acetic acid in Br on either side of the amine/aldehyde proceed smoothly
water (1:1 ratio) at 10 °C for 48 hours.
under our experimental conditions. Another significant
advantage of using CDs is that inside the hydrophobic CD
cavity, the hydrolysis of imines is hindered and conse-
quently there is no need to remove the water formed in the
reaction.
To extend the scope of this Mannich reaction further, var-
ious aromatic aldehydes and aromatic amines along with
propiophenone were employed. The results are given in
Table 2 (entries 1–7). Under the optimized reaction
conditions28 only unsubstituted amines/aldehydes and The scope of the Mannich reaction with aromatic alde-
also those having moderately reactive groups such as hydes and aromatic amines was extended to cyclohexa-
chloro or bromo gave the Mannich products with high none (Table 2, entries 8–12). The reaction was complete
diastereoselectivity (dr up to 98:2). The reaction did not within five hours, and the products were formed in excel-
proceed when strong electron-releasing or electron-with- lent yields (up to 98%) with good anti-diastereoselectivi-
drawing substituents were present in aldehydes or amines ty. The ratio of the anti and syn isomers was determined
(Table 2, entries 6 and 7). In all these cases, it was noticed from the 1H NMR spectra of the products. The J coupling
that the reaction stopped with the formation of the imine. values between the vicinal protons adjacent to C=O and
This may be explained as follows: The key step in the for- NH for the anti-isomer (about 7.5 Hz) were higher than
Table 2 Three-Component Mannich Reaction of Substituted Aromatic Aldehydes and Amines with Propiophenone–Cyclohexanone in the
Presence of β-CD in Water and Acetic Acid at 10 °Ca
Entry
Aldehyde
Amine
Ketone
Time/
h
Yieldc
(%)
dr
ee syn/
(syn/anti) ee anti (%)
1
2
benzaldehyde
4-chloroaniline
aniline
propiophenone
propiophenone
propiophenone
propiophenone
propiophenone
propiophenone
propiophenone
cyclohexanoneb
cyclohexanoneb
cyclohexanoneb
cyclohexanoneb
cyclohexanoneb
48
48
48
60
60
60
60
5
4a (73)
4b (70)
4c (64)
4d (59)
4e (51)
–
98:2d
91:9d
98:2d
86:14d
88:12d
–
2/6d
99/5d
5/0d
90/34d
88/1d
–
benzaldehyde
3
benzaldehyde
4-bromoaniline
4-chloroaniline
4-bromoaniline
4
4-chlorobenzaldehyde
4-chlorobenzaldehyde
5
6
4-nitro/4-methoxybenzaldehyde 4-chloroaniline
7
benzaldehyde
benzaldehyde
benzaldehyde
benzaldehyde
benzaldehyde
benzaldehyde
4-nitro-/4-methoxyaniline
–
–
–
8
4-chloroaniline
aniline
4f (98)
4g (95)
4h (98)
4i (96)
4j (97)
0:100e
0:100e
0:100e
0:100e
35:65e
n.d.
n.d.
n.d.
n.d.
n.d.
9
5
10
11
12
4-bromoaniline
4-fluoroaniline
4-iodoaniline
5
5
5
a Reaction conditions: amine (1 mmol), aldehyde (1 mmol), ketone (1 mmol), CD (0.1 mmol) in AcOH–H2O (1:1).
b Amount of ketone used was 5 mmol.
c Isolated yield.
d Analyzed by HPLC.
e Analyzed by 1H NMR as the products were not separated in HPLC; n.d.: not determined.
Synlett 2012, 23, 2328–2332
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereoselective Mannich Reaction in Water
2331
those for the syn-isomer (about 4.5 Hz).10,30,31 Product iso- In summary, we have established an efficient, atom-eco-
lation was accomplished by simple filtration, as the prod- nomical, acetic acid catalyzed diastereoselective Mannich
ucts were insoluble in water. There was no need for reaction involving propiophenone, aromatic aldehydes
column chromatography as the crude product itself was and aromatic amines using a natural sugar derivative, β-
very pure.
CD, as a chiral inductor at 10 °C. Though the substrate
scope is limited in the present study, to the best of our
knowledge, this is the first report showing a very high
diastereoselectivity (up to 98:2 dr) in a Mannich reaction,
wherein all the three components are aromatic entities.
For example, in a previous report7 involving three aryl
substrates, the maximum diastereomeric ratio of 4:1 was
observed at a temperature of –45 °C using aldehyde, aldi-
mine and the silyl enol ether of propiophenone and this
method also suffered from the drawback that the silyl eno-
lates had to be prepared from the corresponding carbonyl
compounds under anhydrous conditions. Other salient
features of this protocol are: (a) a catalytic amount of in-
expensive β-CD is sufficient for producing excellent dia-
stereomeric ratios, (b) aliphatic cyclic ketones can also be
utilized in this process, (c) product isolation is very easy
and a simple filtration is sufficient, (d) the reaction does
not require preformed enolate equivalents or preformed
imine equivalents (aldimine may be formed in situ in the
presence of water), and (e) the reaction is highly chemose-
lective with respect to the Mannich product and there is no
aldol condensation taking place between the aldehyde and
ketone moieties.
To account for the observed results, a plausible mecha-
nism (Scheme 1) is proposed. Initial formation of an in-
clusion complex of aromatic amine with β-CD is proposed
and this readily forms an imine with the aldehyde. Subse-
quent protonation by acetic acid forms the E-iminium ion
intermediate, which is stabilized by H-bonding with the
secondary hydroxyl groups of β-CD. Inside the CD cavity,
propiophenone forms an E-enol intermediate predomi-
nantly over the Z-enol. This conclusion of both the inter-
mediates is stabilized by the π–π stacking interaction
between the phenyl rings of the imine and the enol and
also by H-bonding with the secondary hydroxyl groups of
β-CD. Subsequent nucleophilic attack resulting in C–C
bond formation occurs via unlike attack (the si-face of the
enol attacking the re-face of the iminium ion or vice ver-
sa) which leads to the formation the syn-isomer. After the
formation of the product, the escape from the CD cavity
occurs readily. In cyclohexanone, the ring cannot be in-
cluded in the CD cavity due to steric reasons, so that it at-
tacks the imine outside of the cavity. This mode of
reaction results predominantly in the anti-isomer.
Scheme 1 Mechanism for acetic acid catalyzed Mannich reaction
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2328–2332

2332
S. Sukumari et al.
LETTER
Chimie 2011, 14, 149.
Acknowledgment
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S.S. gratefully acknowledges UGC, Hyderabad for awarding
Teacher fellowship under FDP-XI plan. Financial support from
DST under FIST is acknowledged.
Supporting Information for this article is available online at
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(28) (a) General Procedure for the Mannich Reaction of
Aldehydes, Amines and Propiophenone: Amine (1 mmol)
was added to β-CD (0.1 mmol) dissolved in H2O (2 mL) and
stirred until the inclusion complex was formed and then
aldehyde (1 mmol), AcOH (2 mL) and propiophenone (1
mmol) were added successively and stirred at 10 °C for 48 h.
A sat. aq NaHCO3 solution was added to the above reaction
mixture, extracted with EtOAc, dried over Na2SO4 and
concentrated. The product was purified either by recrystal-
lization from EtOH–acetone mixture (3:2) or by silica gel
column chromatography (b) Analytical data of a few typical
compounds are given below:
(i)3-[(4-Chlorophenyl)amino]-2-methyl-1,3-
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diphenylpropan-1-one (4a) (Table 2, entry 1):
1H NMR [300 MHz, CDCl3, Me4Si; syn/anti = 98:2
(HPLC)]: δ = 1.20 (d, J = 7.0 Hz, 3 H), 3.92–4.00 (m, 1 H),
4.51 (br s, 1 H), 4.69 (br s, 1 H), 6.37 (d, J = 9.0 Hz, 2 H),
6.96 (d, J = 9.0 Hz, 2 H), 7.24–7.60 (m, 8 H), 7.94 (d, J = 7.5
Hz, 2 H). 13C NMR (75 MHz, CDCl3; syn/anti = 98:2): δ =
11.2, 46.7, 59.2, 114.8, 122.2, 126.7, 127.4, 128.2, 128.7,
128.8, 131.6, 133.4, 136.0, 140.9, 145.7, 202.6. HRMS
(ESI): m/z [M + Na]+ calcd for C22H20ClNO: 372.12; found:
372.42. HPLC: diastereomeric ratio was determined by
HPLC with a Chiralcel OD-H column (n-hexane–
isopropanol, 90:10; flow rate: 0.3 mL/min; λ = 254 nm);
dr (syn/anti) = 98:2.
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(ii) 2-Methyl-1,3-diphenyl-3-(phenylamino)propan-1-
one (Table 2, entry 2): 1H NMR (300 MHz, CDCl3, Me4Si;
syn/anti = 91:9): δ = 1.22 (d, J = 6.9 Hz, 3 H), 3.85–4.15 (m,
1 H), 4.46 (br s, 1 H), 4.75 (br s, 1 H), 6.45 (d, J = 8.4 Hz, 2
H), 6.59–6.63 (m, 1 H), 7.00–7.57 (m, 10 H), 7.95 (d, J = 7.5
Hz, 2 H). 13C NMR (75 MHz, CDCl3; syn/anti = 91:9): δ =
11.4, 46.9, 59.2, 113.7, 117.5, 126.8, 127.2, 128.2, 128.6,
128.7, 128.9, 133.2, 136.3, 141.9, 147.2, 202.7. HRMS
(ESI): m/z [M + H]+ calcd for C22H22NO: 316.16; found:
316.50. HRMS (ESI): m/z [M + Na]+ calcd for C22H21NO:
338.16; found: 338.42. HRMS: m/z [M + K]+ calcd for
C22H21NOK: 354.16; found: 354.33. HPLC: diastereomeric
ratio was determined by HPLC with a chiralcel OD-H
column (n-hexane–isopropanol, 90:10; flow rate: 0.3
mL/min; λ = 254 nm); dr (syn/anti) = 91:9
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Synlett 2012, 23, 2328–2332
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