PPh3-catalyzed Mannich reaction: A facile one-pot synthesis of β-amino carbonyl compounds under solvent-free conditions at room temperature

Article abstract of DOI:10.1007/s11164-013-1478-4

PPh₃ was used as an efficient catalyst for the one-pot three-component Mannich reactions of acetophenone with different aromatic amines and aromatic aldehydes under solvent-free conditions at room temperature. This method provides a novel and improved method for preparing β-amino carbonyl compounds in the absence of acidic catalyst in excellent yield. Little catalyst loading, easy accessibility of the catalyst, mild conditions, and simple work-up procedure are the main features of this protocol.

Full text of DOI:10.1007/s11164-013-1478-4

Res Chem Intermed
DOI 10.1007/s11164-013-1478-4
PPh3-catalyzed Mannich reaction: a facile one-pot
synthesis of b-amino carbonyl compounds
under solvent-free conditions at room temperature
•
Javad Abedini-Torghabeh Hossein Eshghi
•
•
Mehdi Bakavoli Mohammad Rahimizadeh
Received: 24 September 2013 / Accepted: 12 November 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract PPh3 was used as an efficient catalyst for the one-pot three-component
Mannich reactions of acetophenone with different aromatic amines and aromatic
aldehydes under solvent-free conditions at room temperature. This method provides
a novel and improved method for preparing b-amino carbonyl compounds in the
absence of acidic catalyst in excellent yield. Little catalyst loading, easy accessi-
bility of the catalyst, mild conditions, and simple work-up procedure are the main
features of this protocol.
Keywords Mannich reaction Á One-pot Á Triphenylphosphine Á Solvent
free Á b-Amino carbonyl
Introduction
The Mannich reaction is one of the most important fundamental carbon–carbon
bond-forming reactions in organic synthesis [1, 2]. A more appropriate version of
the Mannich reaction involved the one-pot three-component approach that allowed a
wide range of structural variations in the reactants-aldehydes, amines, and ketones
to give b-amino carbonyl compounds. The Mannich reaction is generally carried out
in the presence of different catalysts such as silica-supported ferric hydrogensulfate
[2], silica-supported sulfuric acid [3], chiral Brønsted acid [4], heteropoly acid [5],
ionic liquids [6–11], nanoparticles [12–14], enzymes [15], and bismuth(III) chloride
[16]. Recently, strong Lewis acids of air-stable metallocene bis(perfluorooctane-
sulfonate)s as high-efficiency catalysts for carbonyl-group transformation reactions
have been reported [17]. In this report, we have introduced PPh3 as a novel and
J. Abedini-Torghabeh Á H. Eshghi (&) Á M. Bakavoli Á M. Rahimizadeh
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad,
91775-1436 Mashhad, Iran
e-mail: heshghi@um.ac.ir
123

J. Abedini-Torghabeh et al.
efficient catalyst for condensation of acetophenone with different aromatic
aldehydes and amines (Scheme 1). This three-component Mannich reaction is
carried out under solvent-free conditions at room temperature in excellent yields.
Experimental
Chemicals were purchased from Merck. Melting points were recorded on an Electro
thermal type 9100 melting point apparatus. IR spectra were recorded on a Thermo
Nicolet AVATAR-370-FTIR spectrophotometer. The 1H and 13C NMR spectra
were recorded on a Bruker AC 100 and Bruker DRX-400 Avance spectrometers.
General procedure for the synthesis of compounds 4a–4j
PPh3 (5 mol%) was added to a mixture of aromatic amine (1 mmol), aromatic
aldehyde (1 mmol) and acetophenone (1.2 mmol). The reaction mixture was stirred
at room temperature and the progress of the reaction monitored by TLC. After
completion of the reaction, 2 ml methanol was added, followed by dropwise
addition of water until the product began to precipitate. The mixture was then
filtered by suction and the residue was washed with 0.5 ml petroleum ether. The
solid product obtained was suitable for spectroscopic application without further
purification.
3-Anilino-1,3-diphenyl-1-propanone (4a)
1
Yield: 95 %, mp = 168–169 °C, lit. [18] mp = 168–170 °C; H NMR (CDCl3,
100 MHz): d 7.95 (d, 2H, J = 5.5 Hz), 7.33–7.54 (m, 6H), 7.32 (t, 2H, J = 7.5 Hz),
7.18 (t, 2H, J = 7.5 Hz), 6.70 (t, 1H, J = 7.5 Hz), 6.58 (d, 2H, J = 5.5 Hz), 5.00
(dd, 1H, J1 = 7.5, J2 = 5.5 Hz), 3.52 (dd, 1H, J1 = 16.0, J2 = 7.4 Hz), 3.46 (dd,
1H, J1 = 16.0, J2 = 7.4 Hz). IR (KBr) (tmax, cm-1): 3,372, 1,666, 1,593, 1,513,
1,447.
1,3-Diphenyl-3-(4-toluidino)-1-propanone (4b)
Yield 98 %, mp = 165–168 °C, lit. [19] mp = 167–171 °C; 1H NMR (CDCl3,
100 MHz): d 7.9 (d, 2H, J = 10.0 Hz), 7.28–7.58 (m, 8H), 6.94 (d, 2H,
J = 10.0 Hz), 6.53 (d, 2H, J = 10.0 Hz), 5.02 (dd, 1H, J1 = 7.5, J2 = 5.5 Hz),
3.55 (dd, 1H, J1 = 16.1, J2 = 7.5 Hz), 3.46 (dd, 1H, J1 = 16.1, J2 = 7.4 Hz), 2.26
(s, 3H). IR (KBr) (tmax, cm-1): 3,402, 1,680, 1,620, 1,595, 1,449.
3-(4-Bromoanilino)-1,3-diphenyl-1-propanone (4c)
Yield 92 %, mp = 179–180 °C, lit. [20] mp = 178–180 °C; 1H NMR(CDCl3,
400 MHz): d 7.92 (d, 2H, J = 7.6 Hz), 7.61 (m, 1H), 7.26–7.52 (m, 7H), 7.20 (d,
2H, J = 8.0 Hz), 6.50 (d, 2H, J = 8.4 Hz), 4.98 (dd, 1H, J1 = 5.8, J2 = 5.6 Hz),
3.56 (dd, 1H, J1 = 16.4, J2 = 8.2 Hz), 3.49 (dd, 1H, J1 = 16.8, J2 = 7.6 Hz); 13C
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PPh3-catalyzed Mannich reaction
R1
O
CHO
NH2
NH
O
PPh3 , r.t.
+
+
Solvent-free
R1
R2
R2
4a- 4j
4a) R1= H
R2= H
4f) R1= H
4g) R1= 4-Br
R2= 4-OMe
R2= 4-OMe
4h) R1= 4-NO2 R2= H
4b) R1= 4-Me R2= H
4c) R1= 4-Br R2= H
4d) R1= 4-OMe R2= H
4e) R1= 3-Me R2= H
4i) R1= 4-Br
4j) R1= 4-Br
R2= 4-Cl
R2= 4-iPr
Scheme 1 Synthesis of b-amino carbonyl compounds using substituted aniline, benzaldehyde and
acetophenone in the presence of PPh3 at room temperature
NMR (CDCl3, 400 MHz): d 46.0, 55.3, 116.0, 126.4, 127.6, 128.2, 128.6, 129.0,
131.9, 133.6, 136.6, 142.0, 198.1. IR (KBr) (tmax, cm-1): 3,371, 1,667, 1,596,
1,506, 1,485.
3-(4-Bromoanilino)-3-(4-methoxyphenyl)-1-phenyl-1-propanone (4g)
Yield 90 %, mp = 185–188 °C; 1H NMR (CDCl3, 400 MHz): d 7.88 (d, 2H,
J = 7.6 Hz), 7.56 (m, 1H), 7.42-7.46 (m, 2H), 7.31 (d, 2H, J = 8.8 Hz), 7.14 (d, 2H,
J = 8.8 Hz), 6.85 (d, 2H, J = 8.0 Hz), 6.44 (d, 2H, J = 8.4 Hz), 4.89 (dd, 1H,
J1 = 5.8, J2 = 5.6 Hz), 3.77 (s, 3H), 3.41 (dd, 1H, J1 = 16.4, J2 = 8.2 Hz), 3.45 (dd,
1H, J1 = 16.8, J2 = 7.6 Hz). 13C NMR (CDCl3, 400 MHz): d 46.2, 54.3, 55.3, 114.3,
115.5, 127.4, 128.2, 128.7, 131.8, 133.5, 145.9, 198.3. IR (KBr) (tmax, cm-1): 3,384,
1,670, 1,595, 1,512, 1,289.
3-(4-Bromoanilino)-3-(4-isopropylphenyl)-1-phenyl-1-propanone (4j)
Yield 95 %, mp = 153–155 °C; 1H NMR (CDCl3, 400 MHz) d 7.88 (d, 2H,
J = 7.2 Hz), 7.56 (m, 1H), 7.42–7.46 (m, 2H), 7.31 (d, 2H, J = 8.4 Hz), 7.15 (d,
2H, J = 2.0 Hz), 7.16 (d, 2H, J = 2.4 Hz), 6.45 (d, 2H, J = 8.8 Hz), 4.90 (dd, 1H,
J1 = 5.6, J2 = 5.2 Hz), 3.41 (dd, 1H, J1 = 16.4, J2 = 8.2 Hz), 3.47 (dd, 1H,
J1 = 16.8, J2 = 7.6 Hz), 2.86 (m, 1H), 1.21 (d, 6H, J = 6.8 Hz); 13C NMR (CDCl3,
400 MHz): d 23.7, 24.0, 33.7, 46.1, 54.7, 115.6, 126.2, 126.9, 127.1, 128.2, 128.6,
128.7, 131.8, 133.5, 136.6, 139.5, 145.8, 198.3. IR (KBr) (tmax, cm-1): 3,391, 1,667,
1,626, 1,591, 1,488.
Results and discussion
The reaction of acetophenone (1.2 mmol) with benzaldehyde (1 mmol) and aniline
(1 mmol) was first examined in the presence of 1, 5, and mol% PPh3 in solvent or
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J. Abedini-Torghabeh et al.
Table 1 Optimization of the reaction conditions of PPh3 catalyzed Mannich reaction
Entry
Reaction conditions
Time (h)
Yield (%)
1
PPh3 (10 mol%)/solvent-free
PPh3 (5 mol%)/solvent-free
PPh3 (1 mol%)/solvent-free
PPh3 (10 mol%)/EtOH
PPh3 (5 mol%)/EtOH
4
98
2
4
95
3
4.5
6
90
4
92
5
6
90
6
PPh3 (1 mol%)/EtOH
6.75
5
88
7
PPh3 (10 mol%)/CH3CN
PPh3 (5 mol%)/CH3CN
PPh3 (1 mol%)/CH3CN
Without catalyst/solvent-free
Without catalyst/EtOH
Without catalyst/CH3CN
85
8
5.25
5.5
24
24
24
82
9
80
10
11
12
NIL
NIL
NIL
Reaction condition: acetophenone (1.2 mmol), benzaldehyde (1 mmol) and aniline (1 mmol), room
temperature
NIL not isolated
solvent-free conditions at room temperature (Table 1). Considering the selected
solvents (EtOH as polar protic solvent and CH3CN as a polar aprotic solvent), the
best yield of 4a was obtained in solvent-free conditions in 98 % yield. The structure
of the desired product 4a was confirmed by analysis of spectral data and compared
with the reported data. We further investigated the effect of various amount of PPh3.
An increase in the quantity of PPh3 from 1 to 10 mol% slightly increased the yield
of the reaction from 90 to 98 %.
In order to extent the utility of this methodology, reactions of acetophenone with
different aromatic aldehydes and aromatic amines were examined. These reactions
were carried out in the presence of 5 mol% PPh3 under solvent-free condition at
room temperature. After 3–5 h, excellent yields (88–98 %) of b-amino carbonyl
compounds (4a–4j) were obtained. The results are summarized in Table 2.
Another noteworthy feature of these reactions is that the electron-withdrawing
groups such as –NO2 as well as electron-donating substituents such as –OCH3 result
in products in high yields (Table 2, entries 4 and 6–8). This is also applied to multi-
step reactions in which the rate-determining step varied with the observed electronic
effects of the substituent. Generally, ortho-substituted aromatic amines and aromatic
aldehydes gave traces of the desired products because of large steric hindrance
effect.
A plausible mechanism for the formation of b-amino carbonyl compounds such
as 4a from benzaldehyde and aniline in the presence of PPh3 as catalyst is shown in
Scheme 2. Whereas the imine formation does not need a catalyst, PPh3 may
accelerate this reaction by proton abstraction from tetrahedral intermediate and
produce a counter ion which, by large oxophilicity of the phosphonium ion,
converted easily to imine through a hydroxyl triphenylphosphorane (Ph3PHOH)
123

PPh3-catalyzed Mannich reaction
123

J. Abedini-Torghabeh et al.
123

PPh3-catalyzed Mannich reaction
intermediate. Ph3PHOH can increase the enol contents of acetophenone by proton
transfer to ketone or by a proton transfer to imine followed by proton abstraction
from ketone. Finally, the reaction product is formed from the reaction of either enol
by imine or enolate with iminium ion. The catalyst is regenerated by a-elimination
of water from Ph3PHOH.
To further confirm the proposed mechanism, a number of different reactions
were performed which are shown in Scheme 3. Since no chalcone is formed
from the reaction of benzaldehyde and acetophenone under reaction condition
(entry 2), the product should be formed from the reaction of chalcone with
aniline or imine with acetophenone in the absence of Ph3P (entries 5 and 7).
However, the reaction of aniline with benzaldehyde does not need Ph3P (entry
4). Also, aniline and acetophenone do not react together in these conditions
(entry 3). The product can be formed either from the reaction of an imine with
acetophenone or the reaction of chalcone with aniline under the reaction
condition (entries 6 and 8).
In order to show the merits of this study, we compared our obtained results with
the results reported in the literature (Table 3). It is worth mentioning that this
method is faster and simpler than most of the reported methods. The efficiency,
advantages, and generality of PPh3 as catalyst could be the important features of this
method.
In conclusion, triphenylphosphine has been employed for the first time as an
efficient catalyst for the preparation of b-amino carbonyl compounds by a three-
component Mannich reaction under Solvent free conditions at room temperature.
This method is applicable to a wide range of benzaldehydes and anilines. The
attractive features of this procedure are the mild reaction conditions, high
conversions, and operational simplicity,and the inexpensive, non-acidic, and readily
O
PhCHO
PhNH2
PhNHCHPh
O
PhNHCHPh
H
PHPh3
PPh3
-H2O
OPHPh3
CHPh
Ph
H
N
or
or
HOPHPh3
OPHPh3
OH
CH3COPh
O
Ph
O
NH
H2C
H2C
CPh
CPh
Ph
Ph
CHPh
PhN
H
PhN
CHPh
Scheme 2 Suggested mechanism for the synthesis of b-enaminones and b-enamino esters
123

J. Abedini-Torghabeh et al.
O
CHO
NH2
NH
O
PPh3 , RT
1)
+
+
Solvent-free
O
CHO
PPh3 , RT
2)
3)
No reaction
+
Solvent-free
O
NH2
NH2
PPh3 or Catalyst-free
Solvent-free
No reaction
N
+
CHO
PPh3 or Catalyst-free
4)
5)
+
Solvent-free
O
N
Catalyst-free
Solvent-free
No reaction
+
+
O
NH
O
N
PPh3 , RT
6)
Solvent-free
NH2
O
Catalyst-free
Solvent-free
No reaction
NH
7)
+
NH2
O
O
PPh3 , RT
8)
+
Solvent-free
Scheme 3 Reactivity and chemoselectivity of the present protocol
available catalyst, all of which make it a useful and attractive strategy for the
preparation of Mannich adducts. We hope that this protocol provides a logical base
for enantioselective Mannich reactions by means of chiral phosphines.
123

PPh3-catalyzed Mannich reaction
Table 3 Comparison of b-amino carbonyl compounds formation by PPh3 with literature reported
methods
Entry Product Catalyst
Reaction conditions Time (h)/Yield (%) [Lit.]
1
4a
10 mol% HClO4, 5 wt% TX10
5 mol% PEG-OSO3H
H2O, r.t.
6/92 [18]
10/91 [28]
3.5/89 [29]
9/80 [23]
8/93 [12]
2/99 [25]
H2O, r.t.
Bi(OTf)3Á4H2O (0.01 equiv)
¨
0.04 mol% Troger’s base
CH3CN, 25 °C
H2O, r.t.
10 mol% Cu-np (18 2) nm
MeOH, r.t., N2
10 mol% silicon-based Lewis acid Solvent free, r.t.
10 mol% ZSM-5-SO3H
5 mol% PPh3
Solvent free, 60 °C 5/98 [1]
Solvent free, r.t.
4/95a
2
4b
5 mol% PEG-OSO3H
10 mol% Cu-np (18 2) nm
H2O, r.t.
9/92 [28]
9/97 [12]
3/99 [25]
MeOH, r.t., N2
10 mol% silicon-based Lewis acid Solvent free, r.t.
10 mol% ZSM-5-SO3H
10 mol% HClO4, 5 wt% TX10
5 mol% PPh3
Solvent free, 60 °C 6/97 [1]
H2O, r.t.
8/83 [18]
3/98a
Solvent free, r.t.
H2O, r.t.
3
4
4c
5 mol% PEG-OSO3H
10 mol% ZSM-5-SO3H
5 mol% PPh3
10/78 [28]
Solvent free, 60 °C 7/97 [1]
Solvent free, r.t.
3.5/92a
4d
5 mol% PEG-OSO3H
10 mol% Cu-np (18 2) nm
5 mol% PPh3
H2O, r.t.
9/90 [28]
10/91 [12]
3/98a
MeOH, r.t., N2
Solvent free, r.t.
5
6
4e
4f
10 mol% silicon-based Lewis acid Solvent free, r.t.
2/99 [25]
3/98a
5 mol% PPh3
Solvent free, r.t.
H2O, r.t.
5 mol% PEG-OSO3H
Bi(OTf)3Á4H2O (0.01 equiv)
¨
0.04 mol% Troger’s base
8/95 [28]
3.5/86 [29]
12/70 [23]
9/91 [12]
10/91 [18]
4/91a
CH3CN, 25 °C
H2O, r.t.
10 mol% Cu-np (18 2) nm
10 mol% HClO4, 5 wt% TX10
5 mol% PPh3
MeOH, r.t., N2
H2O, r.t.
Solvent free, r.t.
H2O, r.t.
7
4h
5 mol% PEG-OSO3H
12/78 [28]
12/73 [12]
18/80 [18]
5/88a
10 mol% Cu-np (18 2) nm
10 mol% HClO4, 5 wt% TX10
5 mol% PPh3
MeOH, r.t., N2
H2O, r.t.
Solvent free, r.t.
a
Present study
Acknowledgment We are grateful to the Department of Chemistry, Ferdowsi University of Mashhad,
for financial support (Grant No. 49-P-24-01-89).
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