Highly active nano-MgO catalyzed, mild, and efficient synthesis of amidines via electrophilic activation of amides

Article abstract of DOI:10.1016/j.tetlet.2013.05.096

Nano-MgO catalyzed synthesis of amidine derivatives is developed under solvent-free reaction condition at 70 C. Reusability of the catalyst and shorter reaction time as well as high yields are the advantages of this procedure.

Full text of DOI:10.1016/j.tetlet.2013.05.096

Tetrahedron Letters 54 (2013) 4164–4166
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Highly active nano-MgO catalyzed, mild, and efficient synthesis
of amidines via electrophilic activation of amides
⇑
Vijay Kumar Das, Ashim Jyoti Thakur
Department of Chemical Sciences, Tezpur University (A Central University), Tezpur, Napaam 784 028, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Nano-MgO catalyzed synthesis of amidine derivatives is developed under solvent-free reaction condition
at 70 °C. Reusability of the catalyst and shorter reaction time as well as high yields are the advantages of
this procedure.
Received 8 April 2013
Revised 20 May 2013
Accepted 22 May 2013
Available online 7 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Nano-MgO
Amide
Amidine
SFRC
NOSE
More recently, nano magnesium oxide (MgO) has been utilized
extensively because of its potential applications as catalyst.1 In the
domain of catalysis, MgO has a potent basic property which is
exploited in various organic transformations2 and also allows the
high-yield synthesis of the significant molecules.3 Synchronizing
with the theme of green chemistry,4 syntheses of N-bonded com-
pounds under solvent-free conditions have received much
attention.5
Amidines are significant intermediates in the synthesis of many
biologically active compounds6 and there are many strategies re-
ported in the literature for their synthesis.7 They also serve as
important synthons for the preparation of azacyclic compounds.8
Thus, the synthesis of amidines is still a topic of immense scope.
Here we disclose a practical, convenient, and greener procedure
for the synthesis of amidines under solvent-free conditions at
70 °C catalyzed by nano-MgO (Scheme 1). Ogata et al.9 reported
the synthesis of amidines in the presence of polyphosphoric acid
trimethylsilyl ester by treating amine and amide in equimolar ratio
at 160 °C under nitrogen atmosphere. But lower yield of the prod-
ucts, high reaction temperature, application of corrosive reagent
and its non reusability, and tiresome reaction condition made the
methodology less advantageous. To the best of our knowledge,
there is no report on nano-MgO catalyzed synthesis of amidines.
The study was initiated by the model reaction (Scheme 2) be-
tween 4 (5 mmol, 680 mg) and 5 (5 mmol, 0.45 mL) to give 6 with-
out using any catalyst/solvent at 120 °C (Table 1). Under this
condition, a mixture of unknown compounds was detected (Ta-
ble 1, entry 1). Utilizing 5 mL of solvents (Table 1, entries 2–7)
and conducting the reaction at lower temperature did not lead to
product formation. As indicated in Table 1, when pyridine
(10 mol %) was used as catalyst at 70 °C for this transformation
then 6 was isolated in 7% yield (Table 1, entry 8). This observation
prompted us to opt for the best base catalyst for the synthesis of 6.
Several base catalysts were tested under the current condition but
the reaction could not be improved both in terms of yields and
time (Table 1, entries 9–14). When fully characterized nano-
MgO9 was used under the present conditions, it increased the yield
to a reasonable extent (Table 1, entry 15). To obtain better yield of
6, the catalyst loading was optimized (Table 1, entry 15–18) and it
was found that nano-MgO worked efficiently at 5 mol % (Table 1,
R2
O
C
N
C
H
N
H
N
Nano-MgO
70 °C,SFRC
R1 R2 NH2
+
R1
1
3
2
R1 = Aryl, methyl, cyclohexyl and R2 = Aryl, cyclohexyl
Scheme 1. Synthesis of amidine.
H2N
O
N
C
H
N
Catalyst
H
+
C
N
4
5
6
⇑
Corresponding author. Tel.: +91 267008x5059; fax: +91 (3712) 267005/6.
E-mail address: ashim@tezu.ernet.in (A.J. Thakur).
Scheme 2. Model reaction.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.096

V. K. Das, A. J. Thakur / Tetrahedron Letters 54 (2013) 4164–4166
4165
Table 1
entry 17). When the catalyst was changed to nano-Al2O3 and bulk
MgO at 5 mol % loading under the similar conditions, low yields
were recorded and were found to be inferior to nano-MgO (Table 1,
entries 19–20). Bulk MgO having larger particles with smaller sur-
face area was found to be less reactive than nano-MgO under the
present reaction conditions. Overall, the reaction with nano-MgO
was found to be very clean and no side product/by product (s)
was formed.
Optimization of reaction conditiona
Entry
Catalyst
Solvent
Temp. (°C)
Time (h)
Yield (%)b
c
1
2
3
4
5
None
None
None
None
None
EtOH
MeOH
CH3CN
THF
120
70
70
80
70
80
100
70
70
70
70
70
70
70
70
70
70
70
70
70
20
23
18
20
22
24
16
12
15
19
24
13
17
17
7
NRd
NRd
NRd
NRd
NRd
NRd
7
5
15
10
None
6
None
H2O
With this efficient system in hand, we next extended the scope
of the substrate to various alkyl/aryl amines (Table 2). We found
that the reaction was applicable to a broad range of derivatives.
However, a careful analysis of the results from Table 2 indicates
that amines with electron donating moiety reacted smoothly
requiring less time (Table 2, entries 1–3), but amines substituted
with electron-withdrawing functionality required more time to re-
act (Table 2, entries 4 and 5) providing comparable yields. How-
ever, under the present conditions, in comparison to aryl amines,
cyclohexylamine furnished the desired amidine in good yield (Ta-
ble 2, entry 6). In our studies, aniline was used to accomplish the
corresponding amidine derivatives when treated with N-phenyl-
acetamide and cyclohexanecarboxylic acid phenylamide under
the current reaction conditions (Table 2, entries 7 and 8). When
electron withdrawing groups were present in the amide structure,
the reaction took longer time for the formation of product (Table 2,
entries 9 and 10). This might be due to the steric hindrance pro-
vided by the substituted phenyl groups in amide to the incoming
nucleophile. When the reaction was performed involving both R1
and R2 as a methyl group, it furnished very poor yield (7%).
A tentative mechanism has been proposed for the synthesis of
amidine derivatives (Scheme 3). It is hypothesized that the non-
bonded pair of electron on oxygen atom of carbonyl moiety in
amide possibly co-ordinates to the vacant 3p orbital of Mg2+ of
nano-MgO facilitating the electrophilic activation of amide (I).
Now (II) can attack as a nucleophile to form an intermediate (III).
Finally the elimination of water from (IV) gave rise to the forma-
tion of amidine (V). The activation of the substrate by nano-MgO
has been reported previously.10
7
None
Pyridine
K2CO3
NaOH
KOH
DMSO
SFRC
SFRC
SFRC
SFRC
SFRC
SFRC
SFRC
SFRC
SFRC
SFRC
SFRC
SFRC
SFRC
8e
9e
10e
11e
12e
13e
14e
15e
16f
17g
18h
19g
20g
Et3N
PPh3
Trace
c
c
Imidazole
Nano-MgOi
Nano-MgOi
Nano-MgOi
Nano-MgOi
Bulk MgO
Nano-Al2O3
80
85
94
80
68
70
5
3
9
12
7
j
a
Reaction condition: 4 (5 mmol, 680 mg) and 5 (5 mmol, 0.45 mL), SFRC or sol-
vent (5 mL), stirring.
b
Isolated yields.
Mixture of unknown compounds.
No reaction.
10 mol % catalyst was used.
7 mol % catalyst was used.
5 mol % catalyst was used.
3 mol % catalyst was used.
Particles size (17.4–16.4 nm).
c
d
e
f
g
h
i
j
Particle size (37.4–39.7 nm).
Table 2
Nano-MgO catalyzed synthesis11 of amidine derivatives vide Scheme 1
a
Entry R1
R2
Time
(h)
Yieldb,c
(%)
Melting point
(°C)16
1
2
C6H5
C6H5
3
3
94
94
142.8–144.8
108.1–109.6
C6H5
4-
OCH3C6H4
4-CH3C6H4
4-NO2C6H4
4-ClC6H4
C6H11
C6H5
C6H5
C6H5
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
CH3
C6H11
4-
NO2C6H4
4-ClC6H4
3
5
6
5
5
6
5
93
90
91
85
92
88
89
130.8–131.2
182.7–183.5
140.1–141.3
142.0–142.8
126.3–127.8
110.0–111.7
150.6–153.4
Table 3
Recyclabilitya of nano-MgO
Entry
Catalyst recovery (%)
Time (h)
Yieldb (%)
1st runc
2nd runc
3rd runc
4th runc
99
96
90
84
3
4
6
7
94
94
91
88
10
C6H5
5
88
149.1–149.3
a
a
Reaction condition: 1 (1 mmol) and 2 (1 mmol), Nano-MgO (5 mol %), SFRC,
stirring.
Reaction condition: Nano-MgO (5 mol %),
0.45 mL), SFRC.
4
(5 mmol, 680 mg), 5 (5 mmol,
b
b
Yields refer to the isolated pure products.
Yields refer to the isolated 6.
c
c
Products were characterized by IR and NMR (1H and 13C) spectroscopy, MS and
The recovered catalyst was used under identical reaction conditions to those for
the 1st run.
also by comparing their melting points with the authentic ones.
H
N
R1
H
N
H
N
R1
N
H
H
R2
R2
N
R2
N
R1
H
R2
+
_
N
.
.
R1
O
N
H
OH
O
H
H
(IV)
(III)
(V)
(I)
2-
(II)
2+
Mg
2+
2-
2-
2+
2-
2+
2-
2+
2-
O
O
O
O
O
O
Mg
Mg
Mg
Mg
O
H
H
Scheme 3. Tentative mechanism for the synthesis of amidine.

4166
V. K. Das, A. J. Thakur / Tetrahedron Letters 54 (2013) 4164–4166
Figure 1. Flow sheet representation of catalyst isolation.
Figure 2. (a) UV-Visible spectra and (b) Powder XRD pattern of fresh and reused nano-MgO.
3. Lamb, H. H.; Fung, A. S.; Tooley, P. A.; Puga, J.; Krause, T. R.; Kelley, M. J.; Gates,
In this heterogeneous process, the catalyst was recyclable with
B. C. J. Am. Chem. Soc. 1989, 111, 8367.
4. Anastas, P. T.; Warner, J. C. in Green Chemistry: Theory and Practice; Oxford
University Press: New York, 1998.
a slight loss in its activity (Table 3). After completion of the
reaction (Scheme 2), the catalyst was recovered from the
reaction mixture by adding ethyl acetate (10 mL) under
centrifugation (3500 rpm). The extracted catalyst in this way
was decanted and finally dried in an oven at 100 °C for 7 h. It
5. (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, N. D.; Buriol, L.; Machado, P. Chem.
Rev. 2009, 109, 4140; (b) Walsh, P. J.; Li, H.; de Parrodi, C. A. Chem. Rev. 2007,
107, 2503; (c) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025; (d) Nagendrappa,
G. Resonance 2002, 7, 59; (e) Tanaka, K. Solvent-free Organic Synthesis; Wiley-
VCH: Weinheim, 2009.
6. (a) Gautier, J. A.; Miocque, M.; Farnoux, C. C. In The Chemistry of Amidines and
Imidates; Patai, S., Ed.; John Wiley & Sons: New York, Sydney, Toronto, 1975;
Vol. 5, p 283; (b) Granik, V. G. Russ. Chem. Rev. 1983, 52, 377.
was then reused for the fresh reaction (Fig. 1).
A slight
decrease in catalytic activity was observed with recyclization
(Table 3).
In addition, the powder X-ray diffraction analysis exhibited
identical peaks for both the fresh and recovered nano-MgO
(Fig. 2(b)). However, the intensity of the peaks (220), (311),
(411), and (331) diminished slightly which might be due to loss
during centrifugation and subsequent removal of the supernatant
liquid. The loss of 15.4% of the catalyst9 (Fig. 2(a)) was determined
by UV visible spectroscopy. This might be the reason for a slight
decrease in catalytic activity of the catalyst.
In conclusion, we have demonstrated that nano-MgO is highly
active in catalyzing the mild and efficient synthesis of amidine
derivatives under solvent-free conditions at 70 °C. The method of-
fers several advantages including excellent yields of the products,
safe handling, experimental simplicity, catalyst recyclability, and
cost effectiveness which make it useful.
7. (a)Comprehensive Organic Functional Group Transformations; Katritzky, A. R.,
Meth-Cohn, O., Rees, C. W., Eds.; Pergamon Press: Oxford, 1995; Vol. 5, p 741;
(b) Shriner, R. L.; Neumann, F. W. Chem. Rev. 1944, 35, 351; (c) Santos, M. S.;
Bernardino, A. M. R.; Souza, M. C. Quim. Nova 2006, 29, 1301; (d) Kishore, K.;
Tetala, R.; Whitby, R. J.; Light, M. E.; Hurtshouse, M. B. Tetrahedron Lett. 2004,
45, 6991; (e) Gupta, S.; Agarwal, K. P.; Kundu, B. Tetrahedron Lett. 1887, 2010,
51.
8. Usui, H.; Watanabe, Y.; Kanao, M. J. Heterocycl. Chem. 1993, 30, 551.
9. Ogata, S.-I.; Mochizuki, A.; Kakimoto, M.-A.; Imai, Y. Bull. Chem. Soc. Jpn. 1986,
59, 2171.
10. (a) Das, V. K.; Devi, R. R.; Thakur, A. J. Green Chem. 2012, 14, 847; (b) Das, V. K.;
Devi, R. R.; Thakur, A. J. J. Appl. Catal. A: General 2013, 456, 118; (c) Das, V. K.;
Borah, M.; Thakur, A. J. J. Org. Chem. 2013, 78, 3361.
11. To a two-necked round bottomed flask (50 mL), nano-MgO (5.0 mol %, 2.0 mg)
was added along with the addition of N-phenylbenzamide (1.0 mmol, 197 mg)
and stirred (30 min) on a preset oil bath at 70 °C. After that aniline (1 mmol,
0.91 mL) was added, stirring was continued till the required time (the progress
of the reaction was judged by TLC). The reaction mixture was brought to room
temperature and ethyl acetate (3 ꢀ 10 mL) was added and centrifuged at
3500 rpm to pellet out the nanocatalyst. It was then washed with hot ethanol
(5 ꢀ 10 mL) to remove all the organic impurities. Finally, it was decanted and
dried in an oven at 100 °C for 7 h. Then the catalyst was reused in the next run
in the reaction. Having done this, the reaction mixture (in ethyl acetate) was
washed with water and brine, dried over anhydrous Na2SO4, concentrated in a
rotary evaporator, and finally the crude product was purified by column
chromatography (30% ethyl acetate: hexane as the eluent). All the products
listed in Table 2 are known compounds and have been characterized by
comparing with those reported.10
Acknowledgment
VKD thanks UGC for Rajiv Gandhi National Fellowship.
References and notes
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M. N.; Varma, R. S. Tetrahedron 2007, 63, 3093.
N,N0-Diphenyl-benzamidine (Table 2, entry 1): A off white solid (256.8 mg, 94%);
Rf = 0.35 (30% AcOEt: hexane); 1H NMR (400 MHz, CDCl3, TMS): d 8.45 (br, 1H,
N-H), 7.46–7.52 (m, 15H, Ar–H); 13C NMR (100 MHz, CDCl3, TMS): d 163.7,
153.4, 146.1, 132.5, 131.8, 130.2, 129.3, 128.1, 127.3, 125.0, 122.3, 118.4,
115.7; IR (KBr pellets) m
max: 3356 cmꢁ1 (N–H), 1618 cmꢁ1 (C@N); m/z (GC–MS)
272.13 [M+]; Anal. Calcd (%) for C19H16N2: C, 83.79; H, 5.92; N, 10.29%. Found:
C, 83.73, H, 5.87, N, 10.26%.
2. Hattori, H. Chem. Rev. 1995, 95, 537.