Ethane-1,2-diaminium hydrogen sulfate: Recyclable organocatalyst for onepot synthesis of β-amino ketones by a three-component Mannich reaction

Article abstract of DOI:10.3184/174751914X13939287092503

Ethane-1,2-diaminium hydrogen sulfate was synthesised and characterised by NMR and elemental analysis techniques, and found to exhibit high catalytic efficiency towards one-pot Mannich-type reactions of ketones with aromatic aldehydes and aromatic amines in ethanol. This method has the advantages of mild conditions, availability of starting materials, compatibility with a variety of functionalities, and simple work-up procedures. This catalyst also shows good recyclability and reusability.

Full text of DOI:10.3184/174751914X13939287092503

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 APRIL, 223–225
RESEARCH PAPER 223
Ethane-1,2-diaminium hydrogen sulfate: recyclable organocatalyst for one-
pot synthesis of β-amino ketones by a three-component Mannich reaction
Kiumars Bahramia,b*, Mohammad Mehdi Khodaeia,b, Masoumeh Mohammadia and
Nasrin Babajania
aDepartment of Chemistry, Razi University, Kermanshah 67149-67346, Iran
bNanoscience and Nanotechnology Research Center (NNRC), Razi University, Kermanshah, 67149-67346, Iran
Ethane-1,2-diaminium hydrogen sulfate was synthesised and characterised by NMR and elemental analysis techniques, and
found to exhibit high catalytic efficiency towards one-pot Mannich-type reactions of ketones with aromatic aldehydes and
aromatic amines in ethanol. This method has the advantages of mild conditions, availability of starting materials, compatibility
with a variety of functionalities, and simple work-up procedures. This catalyst also shows good recyclability and reusability.
Keywords: Mannich reaction, β‑amino ketones, ethane‑1,2‑diaminium hydrogen sulfate
With new pharmacological targets continuously being
discovered, novel biologically active leads are urgently needed,
resulting in a search for techniques capable of providing many
medicinally interesting compounds.
Mannich‑type reactions are one of the most classical and
useful methods for the preparation of β‑amino ketones and
aldehydes, which constitute various pharmaceuticals, natural
products, and versatile synthetic intermediates.1–4
The catalysts traditionally used in the direct Mannich
reactions of aldehydes, ketones and aryl amines are Lewis
acids5–8 and Brønsted acids.9–12 Although other catalysts
such as proline,13 Brønsted ionic liquids,14–17 and rare earth
perfluorooctanoates18–19 have also been used for this purpose.
However, in most cases these protocols use hazardous organic
solvents, have long reaction times with low yields, and use large
amounts of catalysts. Toxicity and difficulties in separating
conventional catalysts from the product are coupled with poor
selectivity are other important issues. Owing to the versatile
biological activity of β‑amino ketones, development of an
alternative synthetic methodology is of importance.
In continuation of our research programme to develop
selective and efficient methods in organic synthesis,20–22 we
describe here an eco‑friendly and economical approach to
direct Mannich reactions catalysed by ethane‑1,2‑diaminium
hydrogen sulfate (EDAHS) as a new acidic organic catalyst
(Scheme 1).
reaction proceeded very cleanly at room temperature and the
corresponding β‑amino ketone was obtained in 95% yield
(Table 1, entry 4).
Lower loadings of the catalyst gave a low yield even after a
prolonged reaction time, whilst higher loadings did not cause
any obvious increase in the yield of product but could shorten
the reaction time.
In addition, high temperatures improved the reaction rate and
shortened the reaction time but favoured side reactions. It was
found that room temperature was most suitable for the reaction.
Although the reaction in water afforded the desired product,
the yield was only moderate because of the low solubility of
aldehydes, ketones and amines in water.
The activity of the recycled catalyst was also examined under
the optimised conditions. Thus, after the first run, which gave
Table 1 Effect of increasing amount of EDAHS on synthesis of
1,3-diphenyl-3-(phenylamino)propan-1-one from reaction of benzaldehyde,
aniline and acetophenonea
Ph
O
Ph
H
C O
Ph
Ph
H
COC
+
Ph
N
3
H
Ph NH2
Entry
EDAHS/mmol
Yield/%b
1
2
3
4
0.005
0.07
0.09
0.1
Trace
70
85
95
In order to optimise the reaction conditions, the
condensation of benzaldehyde and aniline with acetophenone
was studied as a model reaction in the presence of varying
amounts of EDAHS in EtOH at room temperature. It was
found that, using benzaldehyde (1 mmol), aniline (1 mmol),
acetophenone (1 mmol) and EDAHS (0.1 mmol) in EtOH, the
aReaction conditions: The reactions were performed with benzaldehyde
(1 mmol), aniline (1 mmol) and acetophenone (1 mmol) for 22 min in EtOH
at room temperature.
bIsolated yield.
O
O
Ar1
R1
CHO
H
R1
H
EDAHS
+
R2
Ar1
°
EtOH, 25 C
R2
H
Ar2
Ar2 NH2
N
H
1
2
4a-k
4l-p
R = aryl, R = H
EDAHS = Ethane-1,2-diaminium hydrogen sulfate
H3NCH2CH2NH3. 2HSO4
1
2
R -R = -(CH2)4-
Scheme 1 EDAHS catalysed Mannich reaction of ketones, aryl aldehydes and aryl amines.
* Correspondent. E‑mail: kbahrami2@hotmail.com
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224 JOURNAL OF CHEMICAL RESEARCH 2014
electron‑donating groups were significantly more nucleophilic
and thus determined the reaction rate. Various acetophenones
bearing different substituents such as p‑Cl and p‑NO2 were all
suitable for the reactions. Furthermore, acetophenone was less
reactive than cyclohexanone and required longer reaction times
to afford the desired products (Table 2, entries 12–16).
1H NMR spectroscopy of the products indicated that these
substrates were converted into the corresponding β‑amino
ketones without undergoing further structural changes in their
functional groups. For example, amino, nitro, halo, and hydroxy
functional groups were compatible with the reaction conditions.
In the case of β‑amino‑cyclohexanones, the stereochemistry
1
was determined by H NMR analysis and by comparison with
known compounds. The reaction proceeded smoothly to afford
the Mannich condensation products in excellent yield with
the anti‑isomer as the major product. Unfortunately, it was
observed that the catalyst system had no catalytic activity for
the reactions when aliphatic aldehydes (such as butyraldehyde)
and aliphatic amines (such as propylamine) were used as
substrates.
A comparison of the catalytic efficiency of EDAHS with
selected, previously known catalysts is shown in Table 3 to
demonstrate that the present protocol is indeed superior to
several of the existing protocols.
In conclusion, we have shown that EDAHS can promote
the preparation of a variety of β‑amino ketones from ketones,
aryl aldehydes, and amines. Although the literature reports a
number of procedures for the preparation of β‑amino ketones,
the excellent yields, simplicity, good availability of starting
materials, compatibility with a variety of functionalities and
ease of isolation of the products make our procedure a practical
alternative. This procedure also overcomes the formation of
unwanted by‑products and should open new possibilities for
medicinal chemistry and material science applications.
Fig. 1 Recyclability of EDAHS for the preparation of 1,3-diphenyl-3-
(phenylamino)propan-1-one.
the desired β‑amino ketone in 95% yield, the recovered catalyst
was subjected to a second Mannich‑type reaction from which
it gave the desired product in 94% yield; the average isolated
yield for eight consecutive runs was 93%, which clearly
demonstrates the practical recyclability of this catalyst (Fig. 1).
The results for the preparation of β‑amino ketones are
summarised in Table 2. As shown, a wide variety of structurally
diverse β‑amino ketones were synthesised with EDAHS
according to optimised reaction conditions. In order to show
the generality and scope of the new protocol, various aromatic
aldehydes with either electron‑withdrawing or electron‑
donating groups were tested. It is clear that the aldehydes react
readily to generate the products in very good yields. In the
present investigation, the aldehydes with electron‑withdrawing
groups showed slightly higher reactivity than the aldehydes
with electron‑donating groups (Table 2, entries 13 and 16).
Aromatic amines bearing p‑Me, p‑Cl, and p‑NO2 groups were
favourable to the reactions. Moreover, aromatic amines with
Table 2 Direct Mannich-type reaction of aromatic aldehydes, anilines, and ketonesa
O
O
R1
Ar1 CHO
H
R1
H
+
R2
Ar1
R2
H
Ar2
Ar2 NH2
N
H
Time/min
Entry
Ketone
Aldehyde
Amine
Product
Anti/sync
M.p./°C
Lit. m.p./°C
(Yield/%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C6H5COCH3
C6H5COCH3
C6H5COCH3
C6H5COCH3
C6H5COCH3
C6H5COCH3
C6H5COCH3
C6H5COCH3
4-ClC6H4COCH3
4-ClC6H4COCH3
C6H5CHO
4-MeC6H4CHO
4-MeC6H4CHO
4-MeOC6H4CHO
4-MeOC6H4CHO
4-Me2NC6H4CHO
4-ClC6H4CHO
4-ClC6H4CHO
4-MeC6H4CHO
C6H5CHO
C6H5NH2
4-MeC6H5NH2
C6H5NH2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
22 (95)
10 (90)
22 (92)
24 (90)
25 (93)
28 (86)
23 (90)
27 (89)
21 (91)
19 (95)
18 (93)
14 (90)
20 (89)
17 (88)
20 (90)
12 (87)
–
–
–
–
–
–
–
–
–
169–17019
132–1346
130–13219
148–1496
156–1587
149–1518
119–1208
147–1488
146–1487
117–1187
114–1157
137–13818
131–13318
191–19327
104–10627
164–16528
170–17119
134–1356
131–13219
148–1506
158–1607
149–1508
118–1198
149–1508
146–1477
119–1207
114–1167
139–14018
133–13418
191–191.723
105.3–105.923
163–16524
C6H5NH2
4-ClC6H5NH2
4-ClC6H5NH2
4-ClC6H5NH2
4-O2NC6H5NH2
4-ClC6H5NH2
C6H5NH2
C6H5NH2
C6H5NH2
4-ClC6H5NH2
C6H5NH2
4-ClC6H4NH2
C6H5NH2
–
–
4-O2NC6H4COCH3 C6H5CHO
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
C6H5CHO
75/25
80/20
70/30
79/21
80/20
4-MeOC6H4CHO
4-HOC6H4CHO
4-MeC6H4CHO
3-O2NC6H4CHO
aThe products were characterised by comparison of their spectroscopic and physical data with authentic samples synthesised by reported procedures.
bYields refer to pure isolated products.
cAnti/syn-ratio measured by 1H NMR spectroscopy analysis of the crude reaction mixture.
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JOURNAL OF CHEMICAL RESEARCH 2014 225
Table 3 Comparison of some of the results obtained with this work and
3-(4-Chloro-phenylamino)-3-(4-methoxy-phenyl)-1-phenyl-propan-
1
1-one (4e): White solid; m.p. 156–158 °C (lit.7 158–160 °C); H NMR
the some reported systems
Conditions[Ref.]
Time/min Yield/%
(400 MHz, CDCl3): δ 3.36 (1H, dd, J=7.5, 15.7 Hz), 3.45 (1H, dd,
J=5.8, 15.7 Hz,), 4.60 (1H, br), 3.78 (3H, s), 4.90 (1H, t, J= 7.5 H z),
6.86–6.50 (4H, m), 7.31–7.08 (4H, m), 7.90–7.42 (5H, m).
Substrate
This work
22 min
10 h
11 h
20 min
10 h
8 h
22 min
10 h
12 h
95
95
95
90
91
87
92
97
93
CeCl3–7H2O/EtOH/r.t.6
BiCl3/EtOH/r.t.7
4a
2-(Phenyl(phenylamino)methyl)cyclohexanone (4l): White solid;
1
m.p. 137–138 °C (lit.18 135–137 °C); H NMR (400 MHz, CDCl3): δ
This work
1.72–1.61 (3H, m), 1.93–1.80 (3H, m), 2.45–2.28 (2H, m), 2.81–2.73 (1H,
m), 4.62 (0.75 H, d, J=7.2 Hz), 4.80 (0.25 H, d, J=4.2 Hz), 6.64–6.51
(3H, m), 7.36–7.04 (7H, m).
4b
4c
CeCl3–7H2O/EtOH/r.t.6
SiO2–OAlCl2/EtOH/r.t.8
This work
CeCl3–7H2O/EtOH/r.t.6
BiCl3/EtOH/r.t.7
We are thankful to the Razi University Research Council for
partial support of this work.
Received 13 December 2013; accepted 11 February 2014
Paper 1302340 doi: 10.3184/174751914X13939287092503
Published online: 2 April 2014
Experimental
The materials were purchased from Sigma‑Aldrich and Merck and
were used without any purification. Melting points were determined
in a capillary tube and are not corrected. H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a Bruker Avance 400
spectrometer using TMS as internal standard.
1
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EDAHS (0.1 mmol, 0.026 g) was added to a mixture of acetophenone
(1 mmol) or cyclohexanone (1 mmol), aryl aldehyde (1 mmol) and
aryl amine (1 mmol) in EtOH (5 mL). The mixture was stirred at
room temperature for the desired time as indicated in Table 2. The
progress of the reaction was monitored by TLC. After the reaction was
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