Reusable 1,2,4-triazolium based bronsted acidic room temperature ionic liquids as catalyst for mannich base reaction

Article abstract of DOI:10.1007/s10562-014-1312-7

Unprecedented examples of 1-alkyl-1,2,4-triazolium methanesulfonate based Bronsted acidic room temperature ionic liquids were synthesized and characterized. Their catalytic activity and efficiency in recyclability and reusability on one pot synthesis of halide substituted β-amino carbonyl compounds are reported. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-014-1312-7

Catal Lett (2014) 144:1507–1514
DOI 10.1007/s10562-014-1312-7
Reusable 1,2,4-Triazolium Based Brønsted Acidic Room
Temperature Ionic Liquids as Catalyst for Mannich Base
Reaction
•
Sankaranarayanan Nagarajan Elango Kandasamy
Received: 3 May 2014 / Accepted: 29 June 2014 / Published online: 16 July 2014
Ó Springer Science+Business Media New York 2014
Abstract Unprecedented examples of 1-alkyl-1,2,4-tria-
zolium methanesulfonate based Brønsted acidic room
temperature ionic liquids were synthesized and character-
ized. Their catalytic activity and efficiency in recyclability
and reusability on one pot synthesis of halide substituted b-
amino carbonyl compounds are reported.
Among the classes of ILs, the chemistry of azolium based
ILs are studied well, particularly imidazolium based ILs
[12–14]. The reason is that the imidazolium based IL’s
chemical and physical properties are easily tunable by
means of changing substitution on nitrogen in the ring and
also using different anions [15, 16]. The literature on
azolium based ILs has shown that the triazolium based ILs,
especially 1,2,4-triazolium based ILs are explored less on
its synthesis and applications in organic reaction [17–20].
The development of economic and environmentally
benign catalyst and also a reaction medium for multi-
component reactions (MCR) to synthesis pharmaceuti-
cally important intermediates is inevitable one [21–23].
Notably, the recent development in ionic liquid catalyzed
one pot synthesis of b-amino carbonyl compounds has
shown a new pavement towards green chemistry. The
formation of b-amino carbonyl compounds via carbon–
carbon bond is interesting, because of its pharmaceutical
importance. These intermediates are used in synthesis of
drugs, which are antimalarial, antitumour and antihyper-
tensive agents [24–28]. It is always preferred to synthe-
size the b-amino carbonyl compounds in one pot.
There are numerous techniques such as, microwave-
assisted synthesis, ionic liquids, ultrasound irradiation,
and solvent-free techniques. Many new catalysts
were used to improve this transformation [29–37]. Three
RTILs, 1-ethyl-1,2,4-triazolium methanesulfonate (TrE-
tHMS, 1a), 1-propyl-1,2,4-triazolium methanesulfonate
(TrPrHMS, 1b), 1-butyl-1,2,4-triazolium methanesulfo-
nate (TrBuHMS, 1c), have been used as catalyst for the
synthesis of b-amino carbonyl compounds for the present
work. The choice of halide-substituted aniline and alde-
hyde in the Mannich base reaction is to provide a col-
lective report for the halide-substituted b-amino carbonyl
compounds.
Keywords Halide substituted Mannich base Á
1,2,4-Triazolium Á Catalyst Á Ionic liquids and Mannich
base
1 Introduction
It is known that adapting the green technology for organic
transformations would reduce the usage of toxic catalyst.
Moreover it reduces the usage of large volumes of volatile
organic solvents which are potential hazards to environ-
ment [1–3]. Different strategies have been developed by
many researchers as part of green technology innovation
[4–7]. In recent years, ionic liquids (ILs), especially room
temperature ionic liquids (RTILs) have shown promising
results to fit in the category of green chemistry [8–11].
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-014-1312-7) contains supplementary
material, which is available to authorized users.
S. Nagarajan Á E. Kandasamy (&)
Department of Chemistry, Vel Tech University,
Chennai 600062, India
e-mail: elangoomc@gmail.com
123

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S. Nagarajan, E. Kandasamy
2.3.2 1-Propyl-1,2,4-triazolium methanesulfonate (1b)
2 Experimental
2.1 General
White and semisolid, (1.9 g, 95 %), Anal. calcd. for C6-
H13N3O3S (207.07): C, 34.77; H, 6.32; N, 20.28; Found: C,
1
34.65; H, 6.28; N, 20.23. H NMR (CDCl3, 400 MHz):
1H NMR and 13C NMR spectra were recorded on a Bruker
AVANCE 400 FT NMR instrument in CDCl3 and DMSO-
d6. Elemental analyses of the compounds were obtained
from thermoquest CE instruments CHNS-O, EA/110
model. Electrospray ionization mass spectrometry (ESI-
MS) spectra were recorded on a Waters Q-TOF Premier
mass spectrometer. IR spectra were recorded as KBr pellets
on a Bruker Vector 22 FT IR spectrometer operating at
13.0 (br 1H, NH), 10.18 (s, 1H, 5CH), 8.67 (s, 1H, 3CH),
4.44 (t, 2H, N-CH2–), 2.85(s, 3H, CH3SO3), 2.0 (m, 2H,
–CH2–CH3), 0.98 (t, 3H, CH3). 13C NMR (CDCl3,
75 MHz): 143.36 (C-3), 141.82 (C-5), 53.26 (N-CH2),
39.67(CH3SO3), 22.50 (CH2–CH2–CH3), 10.65 (–CH3).
ES-MS m/z 112.0870 [M-CH3–SO3]?.
400–4,000 cm-1
. Melting points were measured in
DALAL melting point apparatus, India and corrected.
2.3.3 1-Butyl-1,2,4-triazolium methanesulfonate (1c)
Colorless liquid, (1.9 g, 88 %), Anal. calcd. for C7H15N3-
O3S (221.08): C, 38.00; H, 6.83; N, 18.99; Found: C,
1
37.93; H, 6.80; N, 18.93. H NMR (CDCl3, 400 MHz):
2.2 Materials
Solvents were freshly distilled prior to use and glassware was
dried in oven at 120 °C overnight. Chemicals such as me-
thanesulfonic acid was purchased from Sigma Aldrich and
1,2,4-triazole, ethyl bromide, n-propyl bromide and n-butyl
bromide were purchased from SD fine chemicals, India.
Starting materials for catalysis, such as acetophenone, benz-
aldehyde, 4-methylbenzaldehyde, 4-isopropylbenzaldehyde,
4-flurobenzaldehyde, 4-bromobenzaldehyde, 4-chlorobenz-
aldehyde, aniline, 4-fluroaniline, 4-chloroaniline, 4-bromo-
aniline, 4-bromo-3-fluroaniline were purchased from SRL,
India. All chemicals were used without further purification.
12.7 (br, 1H, NH), 10.05 (s, 1H, 5-CH), 8.81 (s, 1H, 3-CH),
4.49 (t, 2H, CH2–CH2–CH2–CH3), 2.85 (s, 3H, CH3SO3),
1.9 (m, 2H, CH2–CH2–CH2–CH), 1.41 (m, 2H, CH2–CH2–
CH2–CH3), 0.98 (t, 3H, CH2–CH2–CH2–CH3). 13C NMR
(CDCl3, 100 MHz): 143.12 (C-5), 141.29 (C-3), 51.70
(CH2–CH2–CH2–CH3), 39.34 (CH3SO3), 30.69 (CH2–
CH2–CH2–CH3), 19.19 (CH2–CH2–CH2–CH3), 13.23
(CH2–CH2–CH2–CH3). ES-MS m/z: 126.1034 [M-
CH3SO3]?.
2.4 Procedure for Catalysis
2.3 Synthesis of 1-Alkyl-1,2,4-triazolium Based RTILs
Aldehyde (2.0 mmol), aniline (2.0 mmol) and acetophenone
(2.5 mmol) were added to the ethanol solution (1 mL) of
1-alkyl-1,2,4-triazolium mehtanesulfonate salts (0.5 mmol).
The reaction mixture was stirred at ambient temperature till
the completion of reaction. The course of the reaction was
monitored by TLC. Upon completion of catalysis 5 mL of
water was added to the reaction mass and then filtered. The
precipitate was washed with n-hexane.
They were synthesized by direct neutralization method, in
which methanesulfonic acid (10 mmol) was slowly added
into the toluene (10 mL) solution of 1-alkyl-1,2,4-triazole
(10 mmol). The resulting mixture was heated to 80 °C for
12 h. A clear distinct two layer of ionic liquid and the
toluene solution was observed. Then the toluene solution
was decanted. The viscous semisolid was washed with
hexane and dried at 45 °C under vacuum for 2 h.
2.5 Procedure for Recycle
2.3.1 1-Ethyl-1,2,4-triazolium methanesulfonate (1a)
Benzaldehyde (2.0 mmol), aniline (2.0 mmol) and aceto-
phenone (2.5 mmol) were added to the ethanol solution
(1 mL) of 1-alkyl-1,2,4-triazolium mehtanesulfonate salts
(0.5 mmol). The reaction mixture was stirred at ambient
temperature till the completion of reaction. The course of
the reaction was monitored by TLC. Reaction mass was
filtered after completion of the catalysis and few drops of
ethanol was added to the filtrate. The next cycle of catalysis
had been continued with the filtrate.
White and semisolid, (1.6 g, 85 %), Anal. calcd. for C5-
H11N3O3S (193.05): C, 31.08; H, 5.74; N, 21.75; Found: C,
1
30.94; H, 5.72; N, 21.70. H NMR (CDCl3, 400 MHz):
12.24 (br, 1H, NH), 9.76 (s, 1H, 5-CH), 8.60 (s, 1H, 3-CH),
4.33 (q, 2H, CH2–CH3), 2.5 (s, 3H, CH3–SO3), 1.38 (t, 3H,
CH2–CH3). 13C NMR (CDCl3 100 MHz): 142.85 (C-5),
140.64 (C-3), 47.04 (N-CH2), 39.04(CH3–SO3), 13.77
(–CH3). ES-MS m/z: 98.0713 [M- CH3–SO3]?.
123

1,2,4-Triazolium Based Brønsted for Mannich Base Reaction
1509
2.5.1 3-(4-Fluorophenyl)-3-(4-iodophenylamino)-1-
phenylpropan-1-one [Table 3, Entry 10]
133.6, 137.1, 143.3, 144.7, 153.6, 155.9, 197.5. FTIR (KBr,
cm-1): 3393vs, 3077w, 1673vs, 1,490s, 1,288s, 685w.
Colorless solid, (0.72 g, 81 %), Anal. calcd. for C21H17-
FINO (445.03): C, 56.65; H, 3.85; N,3.15; Found: C, 56.22;
2.5.5 3-(4-Bromophenyl)-3-(4-bromophenylamino)-1-
phenylpropan-1-one [Table 3, Entry 19]
1
H, 3.64; N, 3.02; mp 157–159 °C, H NMR (400 MHz,
DMSO-d6): 3.68–3.29 (m, 2H), 5.0 (d, 1H), 6.38 (d,
J = 8 Hz, 2H), 6.49 (d, J = 7.2 Hz, 1H), 7.15 (t,
J = 8.4 Hz, 2H), 7.28 (d, J = 8 Hz, 2H), 7.54 (m, 4H), 7.63
(t, J = 7.2 Hz, 1H), 7.97 (d, J = 8 Hz, 2H). 13C NMR
(100 MHz, DMSO-d6): 46.7, 52.4, 77.0, 115.9, 128.9, 129.0,
133.7, 137.1, 140.0, 147.8, 160.7, 162.7, 197.4. FTIR (KBr,
cm-1): 3308vs, 2906w, 1637vs, 1,605s, 1,453s, 1889w.
Colorless solid, (0.35 g, 77 %), Anal. calcd. for C21H17-
Br2NO (456.97): C, 54.93; H, 3.73; N, 3.05; Found: C,
54.83; H, 3.71; N, 3.02; mp 132–134 °C, 1H NMR
(400 MHz, CDCl3): 3.48–3.28 (m, 2H), 4.64 (s, 1H),
4.89(t, 1H),6.42 (m, 2H), 7.18 (m, 2H), 7.30 (m, 2H), 7.47
(m, 4H), 7.60 (m, 1H), 7.89 (d, J = 7.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3): 46.0, 54.4, 110.0, 115.6, 121.4, 128.2,
132.0, 132.1, 133.8, 136.6, 141.6, 145.8, 197.9. FTIR (KBr,
cm-1): 3325vs, 2924w, 1,655s, 1514w, 1,288s, 985w.
2.5.2 3-(4-Chlorophenyl)-3-(4-fluorophenylamino)-1-
phenylpropan-1-one [Table 3, Entry 12]
2.5.6 3-(4-Bromo-3-fluorophenylamino)-1,
3-diphenylpropan-1-one [Table 3, Entry 31]
Colorless solid, (0.48 g, 68 %), Anal. calcd. for C21H17-
ClFNO (353.10): C, 71.29; H, 4.84; N, 3.96; Found: C,
70.92; H, 4.64; N, 3.85; mp 107–108 °C, 1H NMR
(400 MHz, DMSO-d6): 3.69–3.30 (m, 2H), 5.0 (d, 1H),
6.38 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 7.2 Hz, 1H), 7.37
(m, 4H), 7.53 (m, 4H), 7.62 (t, J = 7.2 Hz, 1H), 7.97 (d,
J = 8.4 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): 46.5,
52.4, 77.1, 115.9, 128.8, 129.1, 131.8, 133.7, 137.5, 143,
147.8, 197.3. FTIR (KBr, cm-1): 3374vs, 3024w, 1671vs,
1,269s, 1,203s, 985w, 3024w.
Colorless solid, (0.63 g, 80 %), Anal. calcd. for C21H17-
BrFNO: C, 63.33; H, 4.30; 20.06; N, 3.52; Found: C, 62.95;
1
H, 4.25; N, 3.42; mp 182–185 °C, H NMR (300 MHz,
DMSO-d6): 3.68–3.29 (m, 2H), 4.99 (m, 1H), 6.42 (m, 2H),
6.77 (d, J = 7.2 Hz, 1H), 7.23 (m, 2H), 7.34 (m, 2H), 7.54
(m, 4H), 7.63 (t, J = 7.2 Hz, 1H), 7.97 (t, J = 7.2 Hz, 2H).
13C NMR (75 MHz, CDCl3): 46.0, 52.6, 91.3, 91.6, 99.9,
100.2, 110.6, 126.8, 132.7, 133.1, 136.5, 143.0, 149.3, 157.1,
196.8. FTIR (KBr, cm-1): 3372vs, 2925w, 1,667s, 1,610s,
1,513s, 1372w, 1,289s, 1,186s, 969w, 810ws.
2.5.3 3-(4-Chlorophenylamino)-3-(4-iodophenyl)-1-
phenylpropan-1-one [Table 3, Entry 15]
2.5.7 3-(4-Bromo-3-fluorophenylamino)-1-phenyl-3-p-
tolylpropan-1-one [Table 3, Entry 32]
Colorless solid, (0.65 g, 92 %), Anal. calcd. for C21H17ClI-
NO (461.00): C, 54.63; H, 3.71; N, 3.03; Found: C, 54.59; H,
3.59; N, 3.01; mp 165–168 °C, 1H NMR (400 MHz, DMSO-
d6): 3.68-3.29 (m, 2H), 5.0 (s, 1H), 6.39 (d, J = 8.5 Hz, 2H),
6.5 (d, J = 6 Hz, 1H), 7.13 (t, J = 8.6 Hz, 2H), 7.27 (d,
J = 8.5 Hz, 2H), 7.53 (m, 4H), 7.62 (t, J = 7.3 Hz, 1H),
7.97 (d, J = 7.4 Hz, 2H). 13C NMR (100 MHz, DMSO-d6):
46.7, 52.4, 77.0, 115.6, 116, 128.9, 129.1, 133.7, 137.4, 140,
147.8, 162.7, 197.4. FTIR (KBr, cm-1):3340vs, 3056w,
1899w, 1287vs, 1655vs, 1,621s, 735w.
Colorless solid, (0.7 g, 85 %), Anal. calcd. for C22H19-
BrFNO (411.:06) C, 64.09; H, 4.64; N, 3.40; Found: C,
63.75; H, 4.44; N, 3.34; mp 141–143 °C, 1H NMR
(300 MHz, DMSO-d6): 2.24 (s, 3H), 3.65–3.26 (m, 2H),
4.96 (m, 1H), 6.37 (m, 2H), 6.7 (d, J = 7.2 Hz, 1H), 7.23
(m, 3H), 7.33 (d, J = 7.8 Hz, 2H), 7.54 (t, J = 7.2 Hz,
2H), 7.66 (t, J = 7.2 Hz, 1H), 7.96 (d, J = 7.2 Hz, 2H).
13C NMR (75 MHz, CDCl3): 20.5, 46.1, 52.4, 91.6,
99.9,100.2, 110.7, 126.4, 127.9, 128.6, 132.6, 133.1, 135.9,
136.5, 139.9, 149.3, 157.1, 160.3, 196.8. FTIR (KBr,
cm-1): 3331vs, 2916w, 1,663s, 1,607s, 1,513s, 1448w,
1,293s, 1009w, 736w.
2.5.4 3-(4-Bromophenyl)-3-(4-chlorophenylamino)-1-
phenylpropan-1-one [Table 3, Entry 18]
Colorless solid, (0.66 g, 80 %), Anal. calcd. For C21H17-
BrClNO (413.02): C, 60.82; H, 4.13; N, 3.38; Found: C,
60.48; H, 4.01; N, 3.29; mp 135–138 °C, 1H NMR
(400 MHz, DMSO-d6): 3.66–3.28 (m, 2H), 4.9 (s, 1H), 6.22
(d, J = 6.6 Hz, 1H), 6.49 (s, 2H), 6.82 (d, J = 7.4 Hz, 2H),
7.35 (d, J = 7.1 Hz, 2H), 7.54 (m, 4H), 7.62 (d, J = 6.3 Hz,
1H), 7.97 (d, J = 6.6 Hz, 2H). 13C NMR (100 MHz,
DMSO-d6): 46.7, 53.2, 114.1, 115.7, 128.7, 129.1, 131.7,
2.5.8 3-(4-Bromo-3-fluorophenylamino)-3-(4-
isopropylphenyl)-1-phenylpropan-1-one
[Table 3, Entry 33]
Colorless solid, (0.66 g, 78 %), Anal. calcd. for C24H23-
BrFNO (439.09): C, 65.46; H, 5.26; N, 3.18; Found: C,
65.32; H, 5.12; N, 3.08; mp 120–122 °C, 1H NMR
123

1510
S. Nagarajan, E. Kandasamy
R1
N
(300 MHz, CDCl3): 1.21 (d, 6H), 3.5–2.84 (m, 3H), 4.91
(m, 1H), 6.33 (m, 2H), 7.19 (m, 3H), 7.31 (m, 3H), 7.43 (t,
J = 7.5 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.89 (d,
J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): 24.3, 33.5,
46.6, 52.8, 92, 100.6, 111.1, 126.9, 128.5, 129.1, 133.6,
137.1, 140.9, 147.4, 149.7, 149.9, 158, 160.4, 197.4. FTIR
(KBr, cm-1); 3390vs, 2964w, 1,670s, 1,611s, 1,516s,
1447w, 1373w, 1,188s, 969w, 687w.
R1
N
N
H
C
3SO3
H
H
C
3SO3
N
N
H
Toluene/80°C
N
Et (1a), Pr (1b), n-Bu (1c)
=
R1
H
Scheme 1 Synthesis of N-alkyl-1,2,4-triazolium mehtanesulfonate
2.5.9 3-(4-Bromo-3-fluorophenylamino)-3-(4-
fluorophenyl)-1-phenylpropan-1-one [Table 3, Entry
34]
128.5, 129.4, 131.7, 133.7, 143.0, 149.6, 197.1. FTIR (KBr,
cm-1): 3,327s, 2928w, 1570br, 1,487s, 1,066s, 821w.
Colorless solid, (0.64 g, 78 %), Anal. calcd. for C21H16-
BrF2NO (415.04): C, 60.59; H, 3.87; N, 3.36; Found: C,
60.33; H, 3.79; N, 3.33; mp 136–138 °C, 1H NMR
(400 MHz, DMSO-d6): 3.68–3.31 (m, 2H), 5.01 (t, 1H),
6.34 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 12.4 Hz, 1H), 6.79
(d, J = 7.2 Hz, 1H), 7.17 (m, 2H), 7.24 (m, 1H), 7.54 (m,
3 Results and Discussion
The RTILs, 1a–c, were synthesized by adopting reported
1
procedure (Scheme 1) and characterized by H NMR, 13C
NMR, ESI-MS and Elemental analysis.In 1H NMR, the
5-CHand3-CHprotonsof1a–c fallintherangeof9.76–10.18
and 8.59–8.81 ppm respectively [38, 39]. In addition positive
ion ESI-MS? gave the corresponding cationic ([M-X]?) peak
for 1a–c. The pH values of 1a–c are 2.22, 2.42 and 2.57
respectively.1 The RTILs, 1a–c, were miscible with polar
protic/aprotic solvents such as water, methanol, ethanol,
dichloromethane, chloroform, dimethylsulfoxide and
dimethylformamide and immiscible with non-polar hydro-
carbon solvents. The knowledge of miscibility helps in
recovering 1a–c and product from the reaction mixture.
The optimization is a crucial step for any kind of organic
reaction; hence we have done a series of reactions with
benzaldehyde, acetophenone and aniline at different reaction
conditions using RTILs as catalyst and reaction medium.
The observation and inference suggested that the addition of
ethanol as solvent and a little excess of acetophenone helped
to improve the yield as well as reduce the course of reaction
(Table 1). The role of 1a–c as reaction medium has been
ignored for these Mannich reactions because it raises few
problems such as recovering of products and incompletion
of reaction due to poor miscibility with reactants (Table 2).
Hence, the optimized reaction condition is 0.5 mmol of
RTIL as catalyst, the ratio of reactants is 2:2.5:2 mmol
(benzaldehyde, acetophenone and aniline) and 1 mL of
ethanol as solvent at room temperature (Table 1).
4H), 7.64 (t, J = 7.2 Hz, 1H), 7.98 (d, J = 8 Hz, 2H). 13
C
NMR (100 MHz, DMSO-d6): 46.5, 52.4, 92.3,100.8,
111.2, 115.7, 128.9, 129.0, 129.1, 133.7, 137.0, 139.6,
149.7, 158.0, 160.4, 162.8, 197.3. FTIR (KBr, cm-1):
3373vs, 2926w, 1,665s, 1,607s, 1,510s, 1419w, 1,330s,
970w.
2.5.10 3-(4-Bromo-3-fluorophenylamino)-3-(4-
chlorophenyl)-1-phenylpropan-1-one [Table 3,
Entry 35]
Colorless solid, (0.680 g, 79 %), Anal. calcd. for C21H16-
BrClFNO (431.01) : C, 58.29; H, 3.73; N, 3.24; Found: C,
57.97; H, 3.68; N, 3.19; mp 140–143 °C, 1H NMR
(400 MHz, CDCl3): 3.49 (m, 2H), 4.82 (s, 1H), 4.89(t, 1H),
6.28 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.35 (m, 4H), 7.47
(m, 2H), 7.60 (m, 1H), 7.89 (d, J = 7.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3): 45.9, 54.3, 101.7, 102.0, 111.1, 127.8,
128.3, 128.9, 129.3, 133.4, 133.9, 136.5, 140.5, 197.0.
FTIR (KBr, cm-1): 3327vs, 2889w, 1,662s, 1599br,
1339w, 1090w.
2.5.11 3-(4-Bromo-3-fluorophenylamino)-3-(4-
bromophenyl)-1-phenylpropan-1-one [Table 3,
Entry 36]
The reactants and RTILs were mixed together and stir-
red. The completion of Mannich reaction was monitored by
TLC. Upon completion of reaction, a small amount of
water was added to the mixture and filtered. The precipitate
Colorless solid, (0.72 g, 77 %), Anal. calcd. for C21H16-
Br2FNO (474.96): C, 52.86; H, 3.38; N, 2.94; Found: C,
52.67; H, 3.27; N, 2.88; mp 120–123 °C, 1H NMR
(400 MHz, DMSO-d6): 3.67–3.32 (m, 2H), 4.98 (s, 1H), 6.32
(d, J = 8.8 Hz, 1H), 6.42 (d, J = 11.6 Hz, 1H), 6.8 (s, 1H),
7.22 (m, 1H), 7.43 (m, 2H), 7.54 (m, 4H), 7.63 (t,
J = 2.4 Hz, 1H), 7.96 (d, J = 7.2 Hz, 2H). 13C NMR
(100 MHz, DMSO-d6): 46.3, 52.5, 92.4, 100.8, 111.2, 120.4,
1
The pH was measured using Digital pH meter Deepvision Model
111/101. All RTILs (5 mmol) were dissolved in triply distilled water
(10 mL) for pH measurement. pH instrument was calibrated with
buffer pH 2.0.
123

1,2,4-Triazolium Based Brønsted for Mannich Base Reaction
1511
Table 1 Optimization of reaction conditions
No.
RTILs
RTILs (mmol)
Solvent
Reactants (mmol)a
Time (hh:mm)
Yield (%)
Temperature (°C)
1
2
3
4
5
6
7
8
9
10
a
1c
1c
1c
1c
1c
1c
1c
1c
1a
1b
0.4
0.4
0.5
0.5
0.5
0.6
0.4
0.5
0.5
0.5
Neat
2:2:2
08:00
01:00
00:40
00:40
00:20
00:20
00:15
00:10
00:25
00:20
65
74
70
80
90
89
60
62
89
88
30
30
30
30
30
30
75
75
30
30
Ethanol
Neat
2:2:2
2:2.5:2
2:2:2
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
2:2.5:2
2:2.5:2
2:2.5:2
2:2.5:2
2:2.5:2
2:2.5:2
Benzaldehyde:acetophenone:aniline
Table 2 Comparison of RTILs and EtOH ? RTILs in Mannich reaction
S. no.
R1
R2
Time (hh:mm)
Yield (%)
Time (hh:mm)
Yield (%)
Time (hh:mm)
Yield (%)
1a
1a ? S
1a
1a ? S
1b
1b ? S
1b
1b ? S
1c
1c ? S
1c
1c ? S
1
2
3
4
5
6
7
8
H
H
00:35
00:40
01:15
01:00
36:00
04:00
02:15
03:15
00:25
00:20
00:50
00:45
24:00
02:45
01:45
03:50
79
75
71
60
10
62
73
69
89
92
84
82
45
85
88
84
00:25
00:20
00:55
00:35
36:00
03:05
02:15
03:00
00:20
00:20
01:00
00:30
20:00
00:55
03:00
02:30
77
75
71
68
30
71
74
69
88
85
85
85
90
88
88
88
00:40
00:25
01:15
00:45
36:00
05:40
01:00
01:40
00:20
00:15
00:45
00:25
24:00
05:50
01:00
01:10
70
82
71
70
43
74
71
70
90
84
86
84
89
88
89
89
H
4-Cl
H
4-Me
4-Me
4-Cl
4-Cl
4-iPr
4-iPr
4-Cl
H
4-Cl
H
4-Cl
S ethanol
Table 3 Results of 1-alkyl-1,2,4-trazolium based RTILs catalyzed Mannich base reactions
S. no. R1
R2
R3
1a
1b
1c
m.p. (°C)b
Time (hh:mm) Yield (%)a Time (hh:mm) Yield (%)a Time (hh:mm) Yield (%)a
1.
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
00:25
02:00
00:20
00:50
00:30
01:00
00:10
00.25
04:45
00:25
24:00
24:00
02:45
02:00
00:05
01:45
89
84
92
88
76
75
77
71
74
80
45
60
85
83
92
89
00:20
03:15
00:20
01:25
00:20
00:45
00:30
00:45
05:45
01:10
20:00
24:00
00:55
01:50
00:05
01:25
88
85
85
89
79
71
70
70
74
77
90
63
88
78
91
90
00:20
01:05
00:25
00:20
00:20
00:55
03:45
05:00
01:30
00:40
24:00
24:00
05:20
02:00
00:03
01:20
90
81
84
88
80
68
74
75
69
81
89
68
88
81
92
89
167–168 [46]
161–162 [49]
169–170 [49]
180–181 [47]
166–167 [53]
110–111 [48]
113–114 [51]
135–136 [51]
154–155 [51]
157–159
2.
H
4-F
4-Cl
4-Br
4-I
3.
H
4.
H
5.
H
6.
4-F
4-F
4-F
4-F
4-F
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Br
H
7.
4-F
4-Cl
4-Br
4-I
8.
9.
10.
11.
12.
13.
14.
15.
16.
H
113–115 [48]
107–108
4-F
4-Cl
4-Br
4-I
117–119 [50]
120–123
165–168
H
132–133 [46]
123

1512
S. Nagarajan, E. Kandasamy
Table 3 continued
S. no. R1
R2
R3
1a
1b
1c
m.p. (°C)b
Time (hh:mm) Yield (%)a Time (hh:mm) Yield (%)a Time (hh:mm) Yield (%)a
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
a
4-Br
4-F
4-Cl
4-Br
4-I
H
H
H
H
H
H
H
H
H
H
H
H
H
H
00:30
01:45
00:45
00:10
00:50
03:05
00:45
01:25
00:40
01:45
00:05
03:50
00:15
00:20
71
75
72
80
84
81
82
85
81
88
81
84
82
79
76
68
75
69
70
72
01:00
01:20
01:30
00:05
01:00
03:15
00:30
01:25
00:35
03:00
00:20
02:30
00:25
00:15
00:20
00:20
01:15
03:05
00:10
04:30
70
77
79
79
85
80
85
85
79
88
78
88
87
80
75
67
71
65
78
75
01:25
01:00
01:25
00:05
00:45
02:30
00:25
00:15
00:20
01:00
03:10
01:10
00:15
00:25
00:20
00:20
00:30
02:00
00:05
03:20
72
80
77
79
86
84
84
82
80
89
77
89
87
81
80
85
78
78
79
77
136–137
4-Br
4-Br
4-Br
4-Me
135–138
132–134
156–158
H
132–133 [49]
141–143
4-Me 4-F
4-Me 4-Cl
4-Me 4-Br
4-Me 4-I
4-iPr
4-iPr
4-iPr
4-iPr
4-iPr
H
163–164
174–175 [47]
163–165 [52]
128–130
H
4-F
4-Cl
4-Br
4-I
132–135
135–137
152–153 [54]
135–138
4-Br 3-F 00:25
182–185
4-Me 4-Br 3-F 00:15
4-iPr
141–143
4-Br 3-F 00:45
4-Br 3-F 02:50
4-Br 3-F 00:15
4-Br 3-F 04:00
120–122
4-F
136–138
4-Cl
4-Br
140–143
120–123
Isolated yields are reported
b
Corrected melting points
was washed with n-hexane and dried (Scheme 2). The
1
products were confirmed by H NMR and melting point.
especially the iodide substituted compounds, were less than
an hour. To the best of our knowledge, the Mannich bases
formed using 4-bromo-3-fluro-aniline are new to literature.
Results of catalysis of RTILs 1a–c have shown that all
three RTILS are compatible with each other. However the
1-butyl-1,2,4-triazolium methanesulfonate (1c) has shown
From the Table 3, it is clear that the yield of halide
substituted b-amino carbonyl compounds were moderate to
good. The duration of completion of reaction of more than
half of halide substituted b-amino carbonyl compounds,
R1
H
3C
O
H
O
O
NH2
NH
1a-c
Ethanol, RT
R3
1a - TrEtHMS
1b - TrPrHMS
1c - TrBuHMS
R1
R2
H, Me, iPr, F, Cl, Br
H, F, Cl, Br, I
H, F
R3
=
=
=
R1
R2
R3
R2
Scheme 2 Mannich base reactions catalyzed by N-alkyl-1,2,4-triazolium mehtanesulfonate
123

1,2,4-Triazolium Based Brønsted for Mannich Base Reaction
1513
Ref.
S. no.
Ionic liquid
Catalyst (mmol)
Solvent
Time (hh:mm)
Yielda
Table 4 Comparison of
different acidic ionic liquids
1
TrBuHMS (1c)
[cmmim][BF4]
[TMBSA]HSO4
[TMBSA]HSO4
[Hmim]SO4
0.5
Ethanol
H2O
00:20
12:00
06:00
06:00
24:00
00:30
12:00
12:00
08:00
02:00
02:00
06:00
90
90
90
94
45
80
85
68
82
82
89
90
2
0.5
[40]
[41]
[41]
[42]
[43]
[35]
[35]
[37]
[44]
[44]
[45]
3
1
H2O
4
1
Ethanol
Ether
Ethanol
Neat
5
1
6
BIL-1
[Hmim]?Tfa
[Hmim]?Tfa
0.1
7
3–4 drops
8
3–4 drops
Ethanol
Neat
9
[Py][CF3COO]
[MPPA][CF3COO]
[MPPA][CF3COO]
[DPPA][HSO4]
13
2.5
2.5
1
10
11
12
Neat
H2O
a
Room temperature and
isolated yield
H2O
Table 5 Reuse of 1-alkyl-1,2,4-triazolium based RTILs in Mannich base reactions
Cycle
1a
1b
1c
Time (hh:mm)
Yield (%)a
Time (hh:mm)
Yield (%)a
Time (hh:mm)
Yield (%)a
Fresh
First
00:20
00:35
00:40
00:45
00:50
90
86
84
82
78
25
35
40
45
50
89
86
84
82
78
20
30
40
50
60
90
86
83
80
80
Second
Third
Fourth
a
Isolated yields
good catalytic performance than the other two (1a and 1b)
RTILs. In general, 1a–c show good catalytic activity in
terms of yield and considerably lesser time to complete the
reaction when compared to reported acidic ionic liquids for
the synthesis of b-amino carbonyl compounds (Table 4).
After completion of catalysis the RTILs 1a–c were able
to recovered from the reaction mixture in good quantity.
Water was added to the reaction mixture and filtered. The
filtrate was concentrated and washed with mixture of n-
hexane and ethylacetate in the ratio of 4:1 and dried in
vacuum. The recovered RTILs were reused for the catalysis
cycle up to four times. Based on isolated yield, the catalytic
activity of 1a–c was not decreased significantly (Table 5).
The yields of halide substituted b-amino carbonyl com-
pounds were good to moderate in all the RTILs. 1a–c, were
efficiently recovered from the reaction mixture without
significant loss of quantity and were reused.
Acknowledgments The authors thank the Department of Science
and Technology—Science and Engineering Research Board (DST-
SERB, SR/FT/CS-60/2011), India for funding. Also the authors thank
Dr. G. Anantharaman, Department of Chemistry, Indian Institute of
Technology Kanpur for ESI-MS measurement.
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