Pronounced catalytic effect of a micellar solution of sodium dodecylsulfate (SDS) upon a three-component reaction of aldehydes, amines, and ketones under neutral conditions

Article abstract of DOI:10.1002/ejoc.200801037

A micellar solution of anionic, cationic or neutral surfactants can be used as an excellent medium for three-component Mannich reactions of aldehydes, amines, and ketones at room temperature. Sodium dodecylsulfate turned out to efficiently catalyze the reaction in neutral pure water (pH ≈ 7), and the corresponding desired β-amino ketones precipitate while the reactions proceedes. This method provides a novel and improved modification of the three-component Mannich reaction in terms of mild reaction conditions, clean reaction profile, improved yields, and excellent regio- and diastereoselectivities with a simple workup. Interesting examples of click chemistry under neutral conditions in water were observed. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200801037

FULL PAPER
DOI: 10.1002/ejoc.200801037
Pronounced Catalytic Effect of a Micellar Solution of Sodium Dodecylsulfate
(SDS) Upon a Three-Component Reaction of Aldehydes, Amines, and Ketones
Under Neutral Conditions
Abbas Ali Jafari,*[a] Fatemeh Moradgholi,[a] and Fatemeh Tamaddon[a]
Dedicated to Professor Habib Firouzabadi on the occasion of his 65th birthday
Keywords: Click chemistry / Green chemistry / Water / Micelles / Surfactants / Mannich bases / β-Amino ketones
A micellar solution of anionic, cationic or neutral surfactants
can be used as an excellent medium for three-component
Mannich reactions of aldehydes, amines, and ketones at
room temperature. Sodium dodecylsulfate turned out to ef-
ficiently catalyze the reaction in neutral pure water (pH ≈ 7),
and the corresponding desired β-amino ketones precipitate
while the reactions proceedes. This method provides a novel
and improved modification of the three-component Mannich
reaction in terms of mild reaction conditions, clean reaction
profile, improved yields, and excellent regio- and diastereo-
selectivities with a simple workup. Interesting examples of
click chemistry under neutral conditions in water were ob-
served.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
sis.[8] They provide β-amino carbonyl compounds, which
are important synthetic intermediates for various pharma-
ceuticals and natural products.[9] The increasing popularity
of the Mannich reaction has been fueled by the ubiquitous
nature of nitrogen-containing compounds in drugs and nat-
ural products.[10] Owing to the importance of β-amino car-
bonyl compounds, numerous methods for the synthesis of
these compounds either by indirect-type or direct-type
Mannich reactions have been reported over the years.[11,12]
The main catalysts reported include Lewis acids such as
metal triflates[8f,8g,11c,11f] and chlorides[8h] and Brøn-
sted[8d,8e,8i,8j,11a,11d,11e,11g] and heteropoly acids.[11h] How-
ever, when ketones rather than their silyl enolates forms are
used directly, Brønsted and Lewis acids require long reac-
tion times and are not effective catalysts. Additionally, in
all previous cases, organic solvent was used as a reaction
medium (co-solvent) and/or for reaction workup. Conse-
quently, these do not represent green protocols. Addition-
ally, vigorous stirring was required for the success of these
reactions due to the poor solubility of the aldehydes,
ketones and amines in water. To solve this problem, surfac-
tants were added to form colloidal dispersions as the reac-
tion media. The use of surfactants not only disperses or-
ganic substrates in water, but can also make organic synthe-
sis possible inside substrate-containing particles in water.[12]
In the course of our investigations to develop new synthetic
reactions in water, we recently have successfully applied the
micellar solution of sodium dodecylsulfate (SDS) to the
hetero-Michael reaction under neutral conditions and pre-
Introduction
Water is a desirable solvent for reasons of cost, safety,
and environmental impact. Moreover, environmental con-
sciousness imposes the use of water for organic processes
from both industrial and academic viewpoints.[1–3] Water
has unique physical and chemical properties, and its use
could enhance the reactivity and selectivity generally
achieved in classical organic solvents.[4] However, organic
solvents are still used instead of water for mainly two
reasons. First, most organic substrates are not soluble in
water, and as a result, water cannot function as a reaction
medium. Second, many reactive substrates, reagents, and
catalysts are sensitive towards water and decompose or be-
come deactivated in aqueous media. A possible way to im-
prove the solubility of substrates is to use surface-active rea-
gents that can form micelles[5] or vesicular structures. The
use of micellar and vesicle-forming surfactants as catalysts
has been investigated in detail for different reactions in
aqueous solutions.[6,7] However, widespread studies in this
area are still needed from both the academic and industrial
points of view.
The Mannich and related reactions are among the most
important C–C-bond-forming reactions in organic synthe-
[a] Department of Chemistry, Yazd University,
Yazd 89195-741, Iran
Fax: +98-351-8210644
E-mail: Jafari@yazduni.ac.ir
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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A. A. Jafari, F. Moradgholi, F. Tamaddon
FULL PAPER
pared sulfoxides by the green oxidation of sulfides in aque- imine and unreacted starting materials. With the aim of im-
ous hydrogen peroxide.[13] Herein, we report a mild, simple, proving the reaction time, we added catalytic amounts of a
efficient, and regio- and stereoselective method for the Brønsted acid or Brønsted base to the reaction mixture in
preparation of β-amino carbonyl compounds by the Man- order to facilitate the formation of an enol from aceto-
nich reaction of ketones with aromatic aldehydes and phenone. In these cases, we observed that the Brønsted acid
amines (the click Mannich reaction) in the presence of SDS or Brønsted base was not necessarily effective; we observed
in pure water under neutral conditions.
no improvement with the combination of SDS and HCl,
Table 1. Optimization of reaction conditions.[a]
Results and Discussion
In order to optimize the reaction conditions with respect
to the reaction medium, temperature, time, and the mole
ratio of the substrates and catalyst, we first studied the
three-component reaction of benzaldehyde (2 mmol), ani-
line (2 mmol) and acetophenone (2 mmol) as a model reac-
tion at room temperature in neutral and acidic water
(Table 1, Entries 1 and 2). The reaction proceeded slug-
gishly, and after a prolonged reaction time (24 h), the corre-
sponding Mannich product was produced in 20% and 25%,
respectively. The problem with the use of water in the reac-
tion (this reaction in water as we have observed) was the
formation of a gummy mass in the reaction medium as pre-
sented in Figure 1. To solve this problem, we performed a
similar reaction in micellar media using SDS and sodium
dodecyl benzenesulfate (SDBS) as anionic micelles, cetyltri-
methylammonium bromide (CTAB), and tetrabutylammo-
nium bromide (TBAB) as cationic micelles and Triton X-
100 as a neutral micelle (Table 1, Entries 3–7). We observed
a drastic rate enhancement when performing this reaction
in water in the presence of 2.5 mol-% of SDS at its critical
micelle concentration (CMC) of 3 to produce the desired
Michael adduct in 96% yield after 6 h. A similar reaction
in the presence of other micellar media (SDBS, CTAB,
TBAB, and Triton X-100) did not proceed to completion
even after 24 h, and the desired adduct was produced in
Entry Solvent
Catalyst (mol-%)
Time [h] Yield [%]
1
2
H2O
H2O
–
24
24
24
24
24
24
6
5
5
6
24
24
24
24
20
25
85
55
20
50
96
85
87
90
5
HCl (5)
SDBS (2.5)
3
4
H2O
H2O
CTMAB (2.5)
TBAB (2.5)
Triton X100 (2.5)
SDS (2.5)
SDS (2.5)/HCl (2.5)
SDS (2.5)/HClO4 (2.5)
SDS (2.5)/NaOH (2.5)
SDS (2.5)
5
6
7
8
H2O
H2O
H2O[b]
H2O
9
H2O
H2O
CH3CN
CH2Cl2
EtOH
solvent-free
10
11
12
13
14
SDS (2.5)
SDS (2.5)
SDS (2.5)
5
8
15
[a] Reaction conditions: solvent (2 mL), room temperature, benzal-
dehyde (2 mmol), aniline (2 mmol), acetophenone (2 mmol). [b]
85%, 55%, 20%, and 50% yields, respectively, together with Under neutral conditions (pH ≈ 7).
Figure 1. Left: The function of SDS micellar droplets and hydrogen bonding is shown for Mannich reactions in pure water (the broken
lines show hydrogen bonds). Right: Photograph of the reaction of acetophenone with benzaldehyde and aniline in an SDS micellar
medium (left) and in pure water (right) after 6 h. In the micellar medium (left), the lower layer is the pure precipitated product and the
upper layer is the SDS micellar solution.
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Mannich Reactions in Micellar Solutions
Table 2. Micellar solutions of SDS-catalyzed direct Mannich reactions of various aryl aldehydes and aromatic amines with acetophenones.
Eur. J. Org. Chem. 2009, 1249–1255
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A. A. Jafari, F. Moradgholi, F. Tamaddon
FULL PAPER
Table 2. (continued.)
[a] All the products were fully characterized by the usual spectroscopic techniques. [b] Isolated yields.
HClO4, or NaOH (Table 1, Entries 8–10). Furthermore, we amino carbonyl compounds in excellent yields (Table 2). In
studied a similar reaction under solvent-free conditions and the case of amines having electron-donating groups, we ob-
in organic solvents such as dichloromethane, acetonitrile, tained the corresponding amino ketones in good yields.
and ethanol at room temperature in the presence of SDS. Amines with electron-withdrawing groups, such as 4-chlo-
We noticed that SDS in these solvents cannot efficiently cat- roaniline, 4-cyanoaniline, and 3-nitroaniline also gave the
alyze the reaction, and the corresponding Mannich product desired products in good yields (Table 2, Entries 4–7). How-
was produced in less than 15% yield after 24 h (Table 1, ever, under these reaction conditions, aldehydes such as cin-
Entries 11–14).
namaldehyde and 4-nitrobenzaldehyde failed to give the
According to the obtained results, the catalytic effect of Mannich products (data not shown).
micellar SDS in the Mannich reaction can be explained as
The high yield, simple reaction protocol, and originality
follows. Aldehydes, amines, and enolizable ketones, which of this process prompted us to use cyclic and linear ali-
are expected to produce β-amino ketones, are hydrophobic phatic ketones under these conditions (Table 3). Thus, we
molecules in aqueous media. In the micellar solution of carried out the three-component coupling reactions with
SDS, the hydrophobic moieties escape from water mole- cyclohexanone (2.5 mmol), aromatic aldehydes (2 mmol),
cules, which encircle the micelle core of SDS. However, they and aromatic amines (2 mmol) at room temperature in
are activated by hydrogen bonding and are pushed by water water in the presence of 5 mol-% of SDS. The correspond-
molecules into the hydrophobic core of the micellar drop- ing Mannich products precipitated as the reaction pro-
lets, where the reactions take place more easily. Water is gressed.
also a sufficiently polar medium to shift the keto-enol equi-
After the consumption of the imines (by the fast in situ
librium to the enol form, which are highly hydrophilic spe- formation from aldehydes and amines) we added water
cies whose formation is the rate-determining step. This ex- (4 mL) to the reaction mixture and isolated the desired
planation is also schematically presented by Figure 1.
products by simple filtration without the formation of any
As shown in Figure 1, when the reaction was complete, side products. We obtained the expected products in moder-
we added water (4 mL) to the reaction mixture and filtered ate yields under these neutral micellar conditions. As the
off and washed with water the precipitated Mannich prod- results show (see Tables 2 and 3), cyclohexanone was more
uct to yield the pure 1,3-diphenyl-3-phenylamino-1-pro- reactive than acetophenone because its enol formation was
panone in 96% yield. This simple workup opened the door much faster, and therefore, the Mannich reactions pro-
to an entirely green, highly efficient, one-pot Mannich reac- ceeded faster.
tion in water.
1
Interestingly, on the basis of the H and 13C NMR, the
After this success, in order to ascertain the generality and Mannich reaction exhibited excellent anti selectivity under
scope of this one-pot Mannich reaction, we observed the these conditions except for the reaction of 2-nitrobenzalde-
reaction of various amines with aldehydes and aceto- hyde, aniline, and cyclohexanone. However, reactions in the
phenones bearing electron-withdrawing and electron-donat- presence of other catalysts in water or organic solvents
ing groups proceed smoothly to give the corresponding β- showed lower stereoselectivity (Table 4).
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Mannich Reactions in Micellar Solutions
Table 3. Micellar solutions of SDS-catalyzed direct Mannich reactions of various aryl aldehydes, aromatic amines and cyclohexanone.
1
[a] All the products were fully characterized by the usual spectroscopic techniques. [b] The syn/anti ratio was determined by H and 13C
NMR spectroscopy.
We determined the diastereoselectivity of the reactions
The reaction of 2-heptanone as an aliphatic unsymmetri-
1
by H and 13C NMR spectroscopy and by comparing our cal ketone with benzaldehyde and aniline proceeded in a
data with that of known compounds reported in the litera- short reaction time with excellent regioselectivity and in high
ture.[8,11] We also performed the reaction of cyclohexanone yield (45 min, 91%). It indicates that the reaction took place
with benzaldehyde and aniline in an acidic SDS micellar at the less-substituted carbon (Scheme 1).
medium to promote the stereoselectivity. The results show
In order to show the merit of the protocol for the Man-
the Brønsted acid enhanced the reaction rate but did not nich reaction, we compared the results obtained using mi-
increase the stereoselectivity. The results are tabulated and cellar solutions of SDS with some of those recently reported
compared with the other catalysts recently reported in in the literature for the reaction of acetophenone, aniline,
Table 4.
and benzaldehyde, as tabulated in Table 5.
Eur. J. Org. Chem. 2009, 1249–1255
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A. A. Jafari, F. Moradgholi, F. Tamaddon
FULL PAPER
Table 4. Investigation of diastereoselectivity of the reaction in
acidic and neutral micellar SDS solution, compared with recently
reported data.
Conclusions
In conclusion, this procedure offers several advantages
for the Mannich reaction such as using water as a green
solvent, low loadings of cheap and commercially available
SDS as a catalyst, neutral conditions (suitable for acid- and
base-sensitive substrates), high yields, excellent regio- and
stereoselectivity, and clean reactions. In addition, product
isolation is easily accomplished by simple filtration, as the
products are insoluble in water. This simple work-up is of
practical importance, especially for large-scale operations.
Experimental Section
Entry Solvent Catalyst
[mol-%]
Time Yield
syn/anti[a] Ref.
General Procedure for the Mannich Reaction: To a solution of SDS
(0.02 , critical micelle concentration: 3.0 ) in H2O (2.0 mL) were
added an amine (2 mmol), an aldehyde (2.0 mmol), and aceto-
phenone (2.0 mmol, 0.24 g) or cyclohexanone (2.5 mmol, 0.25 g)
successively at room temperature. The mixture was stirred
(800 rpm) at the same temperature for the period of time listed in
Tables 2 and 3. Water (4 mL) was added to the reaction mixture,
and the precipitated Mannich base was separated with a simple
filtration. The filtered solid was washed with H2O and dried to
afford the pure products in good to excellent yields. 10 mmol-scale
reactions were also carried out without any difficulties. For exam-
ple, the reaction of benzaldehyde (10 mmol, 1.06 g), aniline
(10 mmol, 0.93 g), and acetophenone (10 mmol, 1.20 g) in the pres-
ence of 2.5 mol-% of SDS afforded the product in 96% isolated
yield after 6 h.
[min]
[%]
1
2
3
4
5
6
7
8
9
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
SDS (5)/HCl (4.6)
SDS (5)/HCl (2.3)
SDS (5)/HCl (1.2)
SDS (5)
10
15
30
45
960
60
240
420
15
85
86
92
93
84
81
83
84
86
35:65
23:77
16:84
4:96
37:63
26:74
44:56
14:86
2:98
–
–
–
–
[11h]
H3PW12O40 (0.12)
DBSA[b] (1)
[12b]
[12c]
[8f]
GFQAS[c] (0.2)/TsOH (10)
Bi(OTf)3·4H2O (5)
EtOH BDMS[d] (10)
[8e]
[a] The syn/anti ratio was determined by H and 13C NMR spec-
troscopy. [b] Dodecylbenzenesulfonic acid. [c] Quaternary ammo-
nium salt gemini surfactants. [d] Bromodimethylsulfonium bro-
mide.
1
4-(3-Oxo-1,3-diphenylpropylamino)benzonitrile (1g): Yield 90%,
white solid, m.p. 151–152 °C. 1H NMR (250 MHz, CDCl3): δ =
3.48 (d, J = 6.2 Hz, 2 H), 5.04 (s, 1 H), 5.27 (br., 1 H), 6.52 (d, J
= 8.5 Hz, 2 H), 7.22–7.59 (m, 10 H), 7.86 (d, J = 8.5 Hz, 2 H) ppm.
13C NMR (62.9 MHz, CDCl3): δ = 45.8, 54.1, 99.2, 113.2, 120.4,
126.2, 127.8, 128.2, 128.8, 129.0, 133.5, 133.7, 136.4, 141.5, 150.2,
197.8 ppm. (KBr): ν = 3388, 2223, 1670 cm–1. C H N O (326.39):
˜
22 18
2
calcd. C 80.96, H 5.56; found C 80.85, H 5.53.
1-(4-Methoxyphenyl)-3-phenyl-3-(phenylamino)propan-1-one
(1i):
Yield 92%, white solid, m.p. 123–125 °C. 1H NMR (250 MHz,
CDCl3): δ = 3.32 (dd, J = 15.8, J = 7.5 Hz, 1 H), 3.43 (dd, J =
15.8, J = 5.2 Hz, 1 H), 3.82 (s, 3 H), 4.96 (dd, J = 7.5, J = 5.2 Hz,
1 H), 6.54 (dd, J = 7.7, J = 0.77 Hz, 2 H), 6.64 (td, J = 7.7, J =
0.73 Hz, 1 H), 6.88 (dd, J = 8.6, J = 0.54 Hz, 2 H), 7.06 (t, J =
7.7 Hz, 2 H), 7.03–7.09 (m, 3 H), 7.27–7.30 (m, 2 H), 7.42 (d, J =
7.35 Hz, 2 H),7.87 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (62.9,
CDCl3): δ = 46.0, 55.0, 55.5, 113.8, 117.7, 122.0, 126.4, 127.3,
128.8, 128.9, 129.1, 130.4, 143.1, 147.1, 163.8, 196.8 ppm. IR
Scheme 1. Regioselective, three-component, Mannich reaction of 2-
heptanone, aniline and benzaldehyde in an SDS micellar medium
at room temperature.
(KBr): ν = 3382, 1659 cm–1. C H NO (331.41): calcd. C 79.73,
˜
22 21
2
H 6.39; found C 79.64, H 6.42.
Table 5. Comparison of the catalytic activity of SDS with those of
different catalysts for the Mannich reaction of benzaldehyde, ani-
line, and acetophenone.
2-[(2-Nitrophenyl)(phenylamino)methyl]cyclohexanone (2b) as
a
syn/anti Mixture: Yield 91%, light yellow solid. 1H NMR
(250 MHz, CDCl3): δ = 1.54–2.99 (m, 8 H), 4.45 (br., NH, 0.4 H),
5.22 (d, J = 3.3 Hz, 0.68 H), 5.5 (br., NH, 0.6 H), 5.61 (d, J =
4.42 Hz, 0.42 H), 6.49–6.56 (m, 2 H), 6.62–6.66 (m, 1 H), 7.03–
7.10 (m, 2 H), 7.32–7.50 (m, 2 H), 7.70–7.94 (m, 2 H) ppm. 13C
NMR (62.9 MHz, CDCl3): δ = 25.0, 25.1, 27.3, 28.1, 28.4, 33.8,
42.3, 43.3, 52.0, 54.5, 55.4, 56.0, 113.2, 113.9, 117.8, 118.3, 124.8,
125.1, 127.9, 128.6, 129.1, 129.3, 130.0, 130.1, 133.1, 133.3, 137.3,
Entry Solvent
Catalyst
Time [h] Yield [%] Ref.
[8g]
1
2
3
4
5
5
6
7
8
PhCH3/C6F5CF3 Yb(OPf)3
12
12
12
10
24
48
18
12
6
98
92
95
81
75
81
76
70
96
[8j]
[8h]
EtOH
EtOH
EtOH
H2O
Silica/sulfuric acid
NbCl5
HCl
PS-SO3H
NaBArF4
H3PW12O40
FQAS/TsOH
SDS
[8i]
[11e]
[12d]
[11h]
[12c]
H2O
H2O
137.9 146.6, 149.8, 210.2, 213.3 ppm. IR (KBr): ν = 3386, 1698
˜
H2O
H2O
cm–1. C19H20N2O3 (324.37): calcd. C 70.35, H 6.21; found C 70.43,
H 6.22.
–
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Mannich Reactions in Micellar Solutions
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47, 9257–9259; e) K. Manabe, Y. Mori, S. Kobayashi, Tetrahe-
dron 2001, 57, 2537–2544; f) J. Itoh, K. Fuchibe, T. Akiyama,
Synthesis 2006, 4075–4080.
1-Phenyl-1-(phenylamino)octan-3-one (3): Yield 91%, light yellow
solid, m.p. 71–73 °C. H NMR (250 MHz, CDCl3): δ = 0.83 (t, J
1
= 6.7 Hz, 2 H), 1.13–1.25 (m, 4 H), 1.45–1.50 (m, 2 H), 2.30 (t, J
= 7.3 Hz, 2 H), 2.88 (d, J = 6.4 Hz, 2 H), 4.53 (br., NH, 1 H), 4.82
(t, J = 6.4 Hz, 1 H), 6.52–6.55 (m, 2 H), 6.65–6.65 (m, 1 H), 7.05–
7.11 (m, 2 H), 7.21–7.37 (m, 5 H) ppm. 13C NMR (62.9 MHz,
CDCl3): δ = 13.4, 22.0, 22.6, 30.8, 43.3, 49.8, 54.0, 113.3, 117.3,
125.8, 126.9, 128.3, 128.7, 142.2, 146.4, 209.3 ppm. IR (KBr): ν =
˜
3375, 1701 cm–1. C20H25NO (295.42): calcd. C 81.31, H 8.53; found
C 81.15, H 8.51.
[8]
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of products.
Acknowledgments
The authors are thankful to the Research Council of Yazd Univer-
sity for financial support.
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Received: October 23, 2008
Published Online: January 20, 2009
Eur. J. Org. Chem. 2009, 1249–1255
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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