Synthesis of unsymmetrical (1,3-diarylimidazolidin-4-yl) (aryl)methanone via Mannich reaction

Article abstract of DOI:10.1016/j.tetlet.2013.05.020

An atom-efficient, catalyst-free and environmentally friendly approach towards the synthesis of 1,3,4-trisubstituted imidazolidines (4a-4p) through a multicomponent reaction involving monophenacyl anilines 1, aromatic amines 2 and formaldehyde 3 has been developed. The reaction proceeds in refluxing ethanol providing higher yields of the imidazolidines.

Full text of DOI:10.1016/j.tetlet.2013.05.020

Accepted Manuscript
Synthesis of unsymmetrical (1,3-diarylimidazolidin-4-yl) (aryl)methanone via
Mannich reaction
Selvam Kaladevi, Nidhin Paul, Shanmugam Muthusubramanian, Subbiah
Sivakolunthu
PII:
S0040-4039(13)00768-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.020
TETL 42920
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
27 March 2013
2 May 2013
5 May 2013
Please cite this article as: Kaladevi, S., Paul, N., Muthusubramanian, S., Sivakolunthu, S., Synthesis of
unsymmetrical (1,3-diarylimidazolidin-4-yl) (aryl)methanone via Mannich reaction, Tetrahedron Letters (2013),
doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.020
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Synthesis of unsymmetrical (1,3-diarylimidazolidin-4-yl)
(aryl)methanone via Mannich reaction
Selvam Kaladevi, Nidhin Paul, Shanmugam Muthusubramanian,
Subbiah Sivakolunthu

Synthesis of unsymmetrical (1,3-diarylimidazolidin-4-yl)
(aryl)methanone via Mannich reaction
Selvam Kaladevi, Nidhin Paul, Shanmugam Muthusubramanian,* Subbiah Sivakolunthu
School of Chemistry, Madurai Kamaraj University, Madurai - 625 021, India.
Abstract
An atom-efficient, catalyst-free and environment friendly approach towards the synthesis of
1,3,4-trisubstituted imidazolidines (4a–4p) through a multicomponent reaction involving
monophenacyl anilines 1, aromatic amines 2 and formaldehyde 3 has been developed. The
reaction proceeds in refluxing ethanol providing higher yields of the imidazolidines.
Keywords: Imidazolidines; Multicomponent reaction; Mannich reaction; Monophenacyl
anilines; Nucleophilic addition.
______________________________________________________________________
* Corresponding author, Tel.: +91 452 2458246; fax: +91 452 2459845;
e-mail: muthumanian2001@yahoo.com

Heterocycles stand for a privileged scaffold within the realm of medicinal and biological
chemistry. Among the nitrogen heterocycles highly-substituted, five-membered systems with
two nitrogen atoms, such as imidazole, imidazoline and imidazolidine include numerous natural
products and pharmaceutical lead.1 Imidazolidines are broad class of bioactive pentagonal
heterocyclic compounds with diverse biological activity such as antibacterial, antitubercular,
antifungal, antiHIV, antileishmanial, antinociceptive, antiinflammatory and analgesic activity.2
Imidazolidines are also found to posses
antimicrobial, anti-Trypanosoma cruzi3 and
schistosomicidal properties,4 hypnotic5 and hypoglycaemic effects.6,1d They can be employed as
precursors for medicinally important imidazolidin-2-ones,7 chiral 1,2-diamines8 and substituted
imidazolidine-2,4-diones9. Some of the medicinally important compounds having imidazolidine
skeleton are shown in Fig. 1. As the imidazolidines have a very reactive methylene group, they
may further be functionalized through condensation with aromatic aldehydes.1d
The popular method available for the preparation of symmetrical imidazolidines involves
the condensation of vicinal diamines with formaldehyde / arylaldehyde in presence of different
catalysts10 with subsequent transformations. The reaction of diethyl oxalate with one equivalent
of two different primary amines followed by hydride reduction and condensation reaction with
formaldehyde11 resulted in unsymmetrical imidazolidines, which can also be accessed by some
other methods.12
Mannich reaction, being one of the most important carbon-carbon bond forming
reaction,13 has been employed in the synthesis of several heterocyclic compounds.14 As a
multicomponent reaction, Mannich reaction can be used to generate a library of compounds with
a wide range of structural variations in each categories for biological screening.15
Multicomponent reaction has been employed as a tool for the eco-friendly approach to the

synthesis of various heterocyclic compounds in our laboratory.16 In continuation, the
construction of the imidazolidine ring through a novel protocol has been planned in the present
investigation. Despite the availability of numerous methods for the synthesis of imidazolidines,
only one report carries information about 1,3-diaryl-4-aroyl substituted imidazolidine, wherein
the compound has been obtained as a byproduct in poor yield.17
A retrosynthetic approach reveals that this compound could be accessed from monophenacyl
aniline and that prompted us to take up the present investigation. Thus the target imidazolidine,
1,3-diaryl-4-aroyl substituted imidazolidine 4, was aimed at by refluxing a mixture of
substituted monophenacyl aniline 1, substituted aniline 2 and formaldehyde solution 3 in the
ratio of (1:1:2) for 3 h in ethanol (Scheme 1).18 Solvents such as water, acetonitrile,
dimethylformamide, tetrahydrofuran, methanol and toluene were tested for their suitability in
this reaction. The cleanest conversion with highest yield was achieved when refluxing the above
mixture in ethanol for 3 h (Table 1). It was also proposed to consider the possibility of carrying
out a pseudo five-component reaction, using aniline and phenacyl bromide to generate the
monophenacyl aniline. Hence a mixture of two moles of aniline, phenacyl bromide and excess
formaledyde was subjected to the reaction condition. The reaction did not go on the expected
line. It is noteworthy that whatever be the ratio of formaldehyde solution with reference to the
other substrates (1 or 2 or excess), only the imidazolidine 4 was obtained. Using the optimal
conditions, differently substituted monophenacyl anilines with different anilines were employed
to create a library of 1,3-diarylimidazolidin-4-yl) (aryl)methanone 4 in 77-94% yield (Table 2,
See Supporting Information for characterization data). It must be mentioned that whenever 4-
nitroaniline was used as the component 2, the reaction has not led to the corresponding 4.

The structures of the imidazolidines 4 were established from 1H, 13C and two dimensional
NMR spectral data as illustrated for a representative example 4d (Fig. 2 & Fig 3). The methylene
hydrogens in between the nitrogen atoms appear as a pair of doublets at 4.72 ppm and 5.07 ppm
with a coupling constant of 2.4 Hz. The poor geminal coupling could be due to the attached
hetero atoms.
The mechanism for the formation of 4 has been envisaged in Scheme 2 in which two
possible paths, route A and B, have been suggested. The imine 5 formed by the reaction of
substituted aniline 2 with formaldehyde 3 could have undergone Mannich type reaction with the
enolic form of monophenacyl aniline 1 resulting in 6. 6 could have reacted with formaldehyde
ultimately yielding 1,3-diarylimidazolidin-4-yl)(aryl)methanone 4 after dehydration. The initial
formation of N-hydroxylmethyl derivative 7 has been proposed in route B. 7 undergoes reaction
with imine 5 resulting in the imidazolidine derivative 4.
Thus a simple methodology for the synthesis of unsymmetrical imidazolidines through
Mannich type reaction using ethanol as a solvent has been developed. The proposed strategy
makes use of readily available low cost substrates with no catalyst.
Acknowledgements
The authors thank DST, New Delhi for assistance under the IRHPA program for providing funds
for creating an NMR facility. Financial support from UGC-BSR-JRF to S. K is gratefully
acknowledged.

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18. General procedure for the synthesis of (1,3-diarylimidazolidin-4-l)(aryl)methanone:
A mixture of monophenacyl aniline (1 mmol), substituted aniline (1 mmol) and excess
formaldehyde solution (0.5 mL) in ethanol (10 mL) was refluxed for 3 h. After completion of the
reaction (TLC), the yellow solid was filtered off and further purified by recrystallization from
ethanol to yield pure 4. Characterization data of (3-(4-chlorophenyl)-1-p-tolylimidazolidin-4-

o
1
yl)(phenyl)methanone (4d): Isolated as colourless solid; m.p. 160 C. H NMR (300 MHz,
CDCl3) δH: 2.27 (s, 3H, CH3), 3.76 (dd, 1H, J = 8.7, 2.4 Hz, CH2), 3.99 (t, 1H, J = 8.7 Hz, CH),
4.72 (d, 1H, J = 2.4 Hz, CH2), 5.07 (d, 1H, J = 2.4 Hz, CH2), 5.49 (dd, 1H, J = 8.7, 2.4 Hz, CH2),
6.46 (d, 2H, J = 8.7 Hz, Ar-H), 6.56 (d, 2H, J = 8.4 Hz, Ar-H), 7.08 (d, 2H, J = 8.4 Hz, Ar-H),
7.17 (d, 2H, J = 8.7 Hz, Ar-H), 7.53 (t, 2H, J = 7.8 Hz, Ar-H), 7.63 (t, 1H, J = 7.8 Hz, ArH),
8.03 (d, 2H, J = 7.8 Hz, Ar- H).13C NMR (75 MHz, CDCl3) δC: 20.3, 50.7, 62.3, 66.7, 112.8,
113.3, 122.7, 127.6, 128.4, 129.0, 129.2, 129.8, 133.9, 134.4, 143.4, 143.6, 196.9. Anal. Calcd
for C23H21ClN2O: C, 73.30; H, 5.62; N, 7.43%. Found C, 73.42; H, 5.55; N, 7.54%.

R
HN
N
N
N
N
O
O
N
NH
O
HN
O
N
R
R
H
bisimidazolidines with bactericidal
activity.
anti-inflammatory and antibacterial activities
R3
R2
Cl
H
N
R4
NH
R1
NH
N
N
N
OH
N
H
O
NH
NNO2
CHNO2
Cl
Cl
N
Cl
N
receptor binding imidazolidines
Antihypertensive Activity
neuroactive insecticides
Figure 1. Medicinally important imidazolidine derivatives.
5.49, dd, 1H, J=8.7, 2.4 Hz
Cl
8.03, d, 2H, J = 7.8 Hz
O
H
62.2
7.17, d, 2H, J=8.7 Hz
7.53, t, 2H, J= 7.8 Hz
196.9
N
66.7
50.7
6.46, d, 2H, J=8.7 Hz
7.63, t, 1H, J= 7.8 Hz
3.99, t, 1H, J=8.7 Hz
N
5.07, d, 1H, J=2.4 Hz
3.76, dd ,1H, J=8.7, 2.4 Hz
4.72, d, 1H, J=2.4 Hz
7.08, d, 2H, J=8.4 Hz
6.56, d, 2H, J=8.4 Hz
CH3
20.3
2.27, s, 3H
Figure 2. Selected 1H and 13C chemical shifts of compound 4d.

Figure 3. Selected HMB Correlations of 4d.
Table 1. Solvent effect on the multicomponent reaction for the formation of 4a.
Entry
Solvent
Time (hrs)
Yield (%)
3
3
1
2
3
4
5
6
7
8
9
EtOH
CH3CN
Water
94b
56a
76b
3
3
3
3
3
3
3
THF
45a
60b
Toluene
Dioxane
MeOH
No reaction
65b
DMF
No reaction
No reaction
Solvent-free
aIsolated yield after purification by column chromatography.
bIsolated yield by filtration and recrystallisation.

Table 2. Synthesis of compounds 4.
Entry compound
Ar
Ar'
R1
Yield
(%)
mp
(˚C)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-Methylphenyl CH3
94
78
92
85
86
89
82
85
77
82
78
90
155
157
171
160
158
159
175
162
145
161
155
168
4-Methylphenyl
Cl
4-Methylphenyl
F
4-Chlorophenyl CH3
4-Chlorophenyl
4-Chlorophenyl
Cl
F
4-Chlorophenyl 4-Methylphenyl CH3
4-Chlorophenyl 4-Methylphenyl Cl
4-Chlorophenyl 4-Methylphenyl OCH3
4-Chlorophenyl 4-Chlorophenyl CH3
4-Chlorophenyl 4-Chlorophenyl OCH3
4-Cyanophenyl 4-Methylphenyl CH3
10
11
12
4j
4k
4l
13
14
15
16
4m
4n
4o
4-Cyanophenyl 4-Methylphenyl
4-Phenylphenyl Phenyl
4-Phenylphenyl 4-Methylphenyl CH3
2-Naphthyl 4-Methylphenyl CH3
F
CH3
85
85
83
82
164
163
165
166
4p
Scheme 1. Synthesis of (1,3-diarylimidazolidin-4-yl)(aryl)methanone.

O
Ar'
Route A
NH
Route B
Ar
H2C O
Ar'
OH
Nuclephilic addition
NH
H
Ar
O
Ar'
N
H
N
Ar
7
OH
R1
Mannich -type
reaction
OH
Ar'
N
O
Ar
Ar'
NH
Ar
OH
H
H
N
H
NH
H
O
6
R1
R1
O
Ar'
O
N
Ar'
Ar
NH
N
Ar
OH
NH
OH
R1
R1
O
Ar'
N
dehydration
dehydration
Ar
N
4
R1
Scheme 2. Plausible mechanism for the formation of (1,3-diarylimidazolidin-4-
yl)(aryl)methanone.