Ultrasound promoted expeditious, catalyst-free and solvent-free approach for the synthesis of N,N′-diarylsubstituted formamidines at room temperature

Article abstract of DOI:10.1016/j.tetlet.2013.06.131

An effortless and efficient protocol was developed for the synthesis of N,N′-diarylsubstituted formamidines under environment-friendly conditions. Ultrasonic energy was employed to obtain the desired products in excellent yields with high purity under solvent-free and catalyst-free conditions. Products were purified by the crystallization technique to avoid excess utilization of organic solvents.

Full text of DOI:10.1016/j.tetlet.2013.06.131

Accepted Manuscript
Ultrasound promoted expeditious, catalyst-free and solvent-free approach for
the synthesis of N,N’-diarylsubstituted formamidines at room temperature
Bashir Ahmad Dar, Syed Naseer Ahmad, Mohammad Arif Wagay, Altaf
Hussain, Nisar Ahmad, Khursheed Ahmad Bhat, Mohammad Akbar Khuroo,
Meena Sharma, Baldev Singh
PII:
S0040-4039(13)01116-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.131
TETL 43184
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
4 May 2013
24 June 2013
26 June 2013
Please cite this article as: Dar, B.A., Ahmad, S.N., Wagay, M.A., Hussain, A., Ahmad, N., Bhat, K.A., Khuroo,
M.A., Sharma, M., Singh, B., Ultrasound promoted expeditious, catalyst-free and solvent-free approach for the
synthesis of N,N’-diarylsubstituted formamidines at room temperature, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.06.131
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Ultrasound promoted expeditious, catalyst-free and solvent-free approach for the synthesis
of N,N'-diarylsubstituted formamidines at room temperature
Bashir Ahmad Dar*a, Syed Naseer Ahmadb, Mohammad Arif Wagaya, Altaf Hussaina, Nisar
a
Ahmad , Khursheed Ahmad Bhatb, Mohammad Akbar Khurooc, Meena Sharmad, Baldev
Singh*a

Ultrasound promoted expeditious, catalyst-free and solvent-free approach for the synthesis
of N,N'-diarylsubstituted formamidines at room temperature
Bashir Ahmad Dar*a, Syed Naseer Ahmadb, Mohammad Arif Wagaya, Altaf Hussaina, Nisar
a
Ahmad , Khursheed Ahmad Bhatb, Mohammad Akbar Khurooc, Meena Sharmad, Baldev
Singh*a
a) Indian Institute of Integrative Medicine(CSIR) ,Canal Road, Jammu 180001 India.
b) Indian Institute of Integrative Medicine (CSIR), Sanatnagar, Srinagar 190005 India.
c) Department of Chemistry University of Kashmir, Hazratbal, Srinagar 190006 India.
d) Department of Chemistry University of Jammu. (J & K) 180004, India.
Corresponding author. Tele: (0191) 2572002, +917298982079 Fax: (0191) 2548607
E-mail: bashir_15_dar@yahoo.com, drbaldev1@gmail.com
Abstract

An effortless and efficient protocol was developed for the synthesis of N,N'-diarylsubstituted
formamidines under environment-friendly conditions. Ultrasonic energy was employed to obtain
the desired products in excellent yields with high purity under solvent-free and catalyst-free
conditions. Products were purified by crystallization technique to avoid excess utilization of
organic solvents.
Keywords; Formamidines, Ultrasonication, Green chemistry, Crystallization
Introduction
Organic compounds containing formamidine scaffold have been studied extensively because of
their significant applications as bioactive molecules,1 synthons for various chemical
transformations,2 chelating or bridging modes,3 building blocks in polymer synthesis,4 ultraviolet
light absorbers,5 bleaching agents for paper,6 ligands in transition metal catalysts for asymmetric
synthesis,7 protecting groups for primary amines8 and support linkers in solid phase synthesis.9
Moreover, formamidines are useful to the physical chemists for dynamic NMR study.10 Some
cryoscopic molecular weight determination experiments have also been reported using the
molecular association property of benzene solution of diarylformamidines.11
Several methods have been reported for the synthesis of formamidines but most
of them involve multi-step procedures and longer reaction times.12 Reduction of carbodiimides
with sodium borohydride to the corresponding formamidines was reported as a suitable synthetic
method,13 but exercise of toxic organic solvents (iso-propanol) could not be avoided in
conducting the reaction or working-up the product. One of the most popular methods for the
synthesis of symmetrical and unsymmetrical formamidines is the exchange of N,N-

dimethylformamidines or acetamidines by different amines.14 The negative aspect of this
protocol remains in the utilization of protic organic solvents and high temperature.15 Other
methods involve use of acid chlorides,16 aldehydes,17 o-dinitrobenzene,18 Gold’s reagent19 and 2-
nitroanilines20 as the starting materials. Taylor et al.,13 have reported a general synthetic method
for the synthesis of formamidines by the reaction of triethylorthoformate or orthoacetate with a
number of aliphatic and aromatic amines in acetic acid under reflux at 140°C - 150°C. For the
advancement of this protocol different catalytic systems like FeCl3,21 -Cyclodextrin,22 sulfated
zirconia,23 cerric ammonium nitrate 24 and fluorinated solvent 25 etc have been investigated. The
beneficial effect of base in non-protic solvents for these transformations has also been reported.26
Unfortunately, these protocols have suffered from several problems such as the use of toxic
organic solvents (either in conducting of reaction or working-up of product), high temperatures,
low reaction rate, strong acidic conditions, low yields of the products, tedious work-up and
application of excess amounts of reagents. Therefore, highly efficient and environmentally
benign procedure to prepare N,N-diarylformamidines is still demanded.
Application of ultrasonic energy in chemical transformation is an attractive
and effective approach to solve the problem of poor reaction rate.27The main cause of low
reaction rate is due to poor contact between the reactants and poor mass transfer. Subjecting
reaction mixture to the ultrasound irradiation coerces the fluids to generate huge number of
cavitation bubbles which grow rapidly and subsequently undergo violent collapse. These
vigorous collapses result in the creation of micro-jets that can produce fine emulsion between the
reactants. Moreover, these collapses also lead to the amplification in the local temperature within
the reaction mixture.28Many chemical reactions can be conducted smoothly by sonication to
afford improved yields and increased selectivity. Thus, the ultrasound irradiation has been

established as an important technique in organic synthesis.29 In continuation of our interest in
ultrasound assisted organic reactions, 30 we herein describe the ultrasound promoted procedure
for the synthesis of N,N'-diarylsubstituted formamidines with different species of aryl amines, in
catalyst-free and solvent-free conditions (Scheme 1). The rapid kinetics under mild conditions,
simple work-up and easy purification are added advantages of this protocol.
Scheme 1
In a preliminary experiment, we attempted one pot coupling of 4- methoxyaniline (2 mmol),
triethylorthoformate (1mmol) as the model reaction to optimize the reaction conditions. The
reaction proceeded efficiently with 100% conversion to afford the corresponding
diarylformamidines (98% yields) within short time (50 min) at room temperature (Scheme 1). No
chromatographic technique was used for product purification; the desired products were purified
through crystallization to avoid the excess use of volatile organic solvents. Moreover this method
avoids the exposure of silica gel which is responsible for the decomposion of formamidines to
the corresponding amines.31
Performing the model reaction under stirring conditions at room temperature without
ultrasonic radiation furnished traces of the product even after 24 h, both with and without solvent
(Table 1, entry 1–2). Increasing temperature up to 100 oC under stirring conditions in the absence
of ultrasound radiations could yield only 41% after 24 h reaction time under solvent-free
conditions. Stirring the reaction mixture at 100 oC using DMSO as solvent yielded 46% of the

desired product in 24 h reaction time (Table 1, entry 5–6). The ultrasonic energy thus might be
the major reason for the high efficiency of the one-pot and solvent-free reactions.
Table 1
Reaction of 4-methylaniline with triethylorthofornate under different reaction conditions
Condition
Solvent
DMSO
Entry
Time
24 h
Yielda(%)
Traces
Traces
98
1
2
3
4
5
6
Stirring at 30 oC
Stirring at 30 oC
Sonication at 30 oC
Sonication at 30 oC
Stirring at 100 oC
Stirring at 100 oC
No solvent
No solvent
DMSO
24 h
50 min
90 min
12 h
91
No solvent
DMSO
21
12 h
27
a = HPLC Yield calculated based on the integration of the analytical HPLC signals
Screening of different solvents such as water, ethanol, methanol, dichloromethane, N,N-
diethylformamide, toluene, hexane, acetonitrile for this reaction and their comparison with the
solvent-free approach proved that better results are obtained in solvent-free conditions (Table 2,
entry 1–12).
Table 2.

Effect of solvents on the reaction of 4- methoxyaniline and triethylorthoformate under
ultrasonication.
Entry Solvent
Time(min)
50
Yielda(%)
1
Solvent-free
98
72
91
75
84
71
88
75
72
69
66
49
2
Hexane
90
3
Dimethylsulfoxide
Tetrahydrofuran (THF)
Dimethylformamide
Acetone
90
4
100
100
120
100
90
5
6
7
Acetonitrile
Methanol
8
9
Toluene
120
120
90
10
11
12
Dichloromethane
Ethanol
Water
120
a = HPLC Yield calculated based on the integration of the analytical HPLC signals
Having optimized reaction conditions in hand we attempted to study the scope and the
limitations of this novel method, we investigated the reaction using several electron-donating and
electron-withdrawing substituted anilines with triethylorthoformate under solvent-free

conditions. The reaction was found compatible with various functional groups such as F, Cl, Br,
I, OMe, NO2, CF3 and CN with excellent chemoselectivity (Table 3, entries 3-8 & 12-14). All
the respective products were formed very easily. Anilines substituted with electron donating
groups were observed to require lesser time than the anilines substituted with electron
withdrawing groups. No significant improvement in the yield of the products was observed for
low yielding reactions (e.g., Table 3, entry 5), (Fig. 1) even after longer reaction times. Upon
conducting these reactions under conventional stirring, very low product yields were obtained
even after 12-18 h. So it is clear that the reaction times are reduced to a great extent and the yield
of the products is increased under ultrasonic irradiation without using any catalyst in all the
cases. Based on the results of this study, it seems that the ultrasound radiations are sufficient to
drive this reaction in the absence of any catalyst with decreased reaction times and improved
yields of desired products.
Figure 1. Effect of reaction time on the yield.

Further we extended this methodology for the synthesis of bBbenzimidazoles and
the experiments revealed that a similar procedure is also applicable for the preparation of a wide
range of benzimidazole analogous (Scheme 2).
Scheme 2
This method is equally effective with the substrates bearing electron withdrawing as well as
electron donating groups on the aromatic ring (Table 3, entry 15-17). Benzimidazole
heterocycles are very important bioactive compounds which are known to show antiviral,
antihypertension, anticancer properties.32 A typical procedure for one-pot synthesis of N,N'-
diarylsubstituted formamidines is given in refrences section.33
Table 3. Synthesis of N,N’-diarylformamidines.
Yielda %
Stirring Sonication
Aniline
Entry
Product
Time
Stirring at 100 Sonication at R.T.
oC

12 h
12 h
50 min
50 min
21
27
98
98
1
2
12 h
15 h
15 h
12 h
70 min
70 min
80 min
50 min
9
81
78
69
98
3
4
5
6
10
10
27
16 h
90 min
6
64
7
16 h
12 h
90 min
50 min
7
67
96
8
9
18

16 h
100 min
9
72
10
11
16 h
15 h
100 min
80 min
11
12
84
86
12
12 h
12 h
80 min
50 min
14
24
78
95
13
14
18 h
120 min
9
66
15
16
18 h
18 h
120 min
120 min
12
8
67
62
17
18
19
18 h
18 h
Conditions: a= HPLC Yield calculated based on the integration of the analytical HPLC signals.
Under conventional stirring the reactions were carried out in DMSO medium.

In conclusion, we have developed a mild and efficient method for the synthesis of formamidine
and benzimidazole derivatives using various electronically and structurally divergent amines in
good to excellent isolated yields. In comparison to the methods using potentially hazardous
catalysts or additives, this method is inexpensive, easy to handle, requires short reaction times,
avoids the use of any base, metal/acid catalyst with no side reaction, provides easy product
purification by non-aqueous work-up. Further studies and efforts to extend the scope of this
method for other useful reactions are currently underway.
1H, 13C NMR of some representative compounds is provided in supplementary information.
Acknowledgments
B. A. D. thanks CSIR, New Delhi for awarding the senior research fellowships.
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33 Typical procedure for one-pot synthesis of N,N'-diarylsubstituted formamidines:
A mixture of trimethyl orthoformate (1 mmol), amine (2 mmol) (Scheme 1) or O-
phenylenediamine (1.3 mmol) (Scheme 2) was taken in a 5 ml glass test tube with total reaction
volume 0.4– 0.5 ml approximately. The reaction mixture was placed at room temperature for
specified time under ultrasonic irradiation, performed in a Bandelin Sonorex Super RK 510 H
ultrasonic bath with inner tank dimensions; l x w x d: 300 x 240 x150 mm, Exterior dimensions;
l x w x h: 325 x 265 x 305 mm, Frequency: 35 kHz and Ultrasonic peak output: 640W⁄. Progress
of the reaction was monitored by TLC (silica gel). After completion of the reaction the mixture
concentrated under reduced pressure. To calculate the reaction yield an aliquot (1 mg) of the
reaction mixture was dissolved in methanol (1 ml) and subjected to HPLC analysis (Agilent 1100

series, mobile phase- water containing 0.5%acetic acid and acetonitrile in gradient system, flow
rate-0.7 ml/min, column-RP-18, column temp.-300, wavelength-254nm) and percentage yield of
compound was obtained based on calculated peak area. The crude product thus obtained was
purified by the process of crystallization to afford the corresponding pure N,N'-diarylsubstituted
formamidines or respectively the benzimidazole in good to excellent yields. The physical data
(1H, 13C NMR, HRMS and IR) of these known compounds were found to be identical with those
reported in the literature.