Magnetic Fe3O4-BF3: Highly efficient Lewis acid catalyst for the synthesis of α-aminonitriles

Article abstract of DOI:10.1007/s11164-015-2246-4

Fe₃O₄ magnetic nanoparticle-supported BF₃ was prepared as a new magnetically separable Lewis acid catalyst and successfully used for the one-pot synthesis of α-aminonitriles. A broad range of substrates including the aromatic and heteroaromatic aldehydes, cyclic ketones (cyclopentanone, cyclohexanone and cycloheptanone), aryl-alkyl ketones, diaryl ketones and tetralones, isatin derivatives and acenaphthenequinone were condensed with amines (aliphatic and aromatic) and trimethylsilyl cyanide. All reactions were completed in short times and products were obtained in good to excellent yields. The catalyst could be recycled and reused several times without any loss of efficiency. Finally, α-aminonitrile containing adenine was successfully synthesized.

Full text of DOI:10.1007/s11164-015-2246-4

Res Chem Intermed
DOI 10.1007/s11164-015-2246-4
Magnetic Fe3O4–BF3: highly efficient Lewis acid
catalyst for the synthesis of a-aminonitriles
Mohsen Shekouhy1 Ali Moaddeli2 Ali Khalafi-Nezhad1
•
•
Received: 27 April 2015 / Accepted: 25 August 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Fe3O4 magnetic nanoparticle-supported BF3 was prepared as a new
magnetically separable Lewis acid catalyst and successfully used for the one-pot
synthesis of a-aminonitriles. A broad range of substrates including the aromatic and
heteroaromatic aldehydes, cyclic ketones (cyclopentanone, cyclohexanone and
cycloheptanone), aryl–alkyl ketones, diaryl ketones and tetralones, isatin derivatives
and acenaphthenequinone were condensed with amines (aliphatic and aromatic) and
trimethylsilyl cyanide. All reactions were completed in short times and products
were obtained in good to excellent yields. The catalyst could be recycled and reused
several times without any loss of efficiency. Finally, a-aminonitrile containing
adenine was successfully synthesized.
Keywords a-Aminonitrile Á Fe3O4–BF3 magnetic nanoparticle Á Diversity-
oriented synthesis Á Magnetically separable catalyst Á Lewis acid catalysis
Introduction
The main focus of catalysis research in the past decade has been to enhance catalytic
activity and selectivity and there has not been not any serious attention given to
catalyst recovery. In spite of the fact that homogeneous catalysts are well defined on
a molecular level and are readily soluble in reaction mediums and such single-site
catalysts are highly accessible to the substrates with high catalytic activity and
selectivity, removing then from reaction mixtures to avoid contamination of the
product requires expensive and tedious purification steps [1–4]. So, recycling of
&
Ali Khalafi-Nezhad
khalafi@chem.susc.ac.ir
1
2
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
Department of Chemistry, Yazd University, Yazd 89195-741, Iran
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M. Shekouhy et al.
homogeneous catalysts is an important issue in the sustainable and large-scale
production of fine chemicals. Liquid–liquid and solid–liquid separation are two
major methods for the separation of catalysts form reaction media. Solid–liquid
techniques are based on the immobilization of species with catalytic activity on
solid supports containing organic polymers or resins and inorganic oxide. In the case
of solid particles suspended in a liquid, the rate of transfer of reactants within the
liquid to the catalyst is inversely proportional to the particle diameter. Thus, the
activity (and the selectivity) of the suspended catalyst will benefit from decreasing
the particle size [5]. It is worth mentioning at this point that the dispersion of most
conventional heterogeneous catalysts in liquid media is poor and, in most cases,
distinct solid–liquid separation occurs even after vigorous stirring. One way to
overcome this drawback is to keep the size of the particles as small as possible
[6–13]. However, particles with diameters of less than 100 nm are difficult to
separate by filtration techniques and, in such cases, expensive ultracentrifugation is
often the only way to separate product and catalyst. One important way to overcome
this mistake is the application of magnetic nanoparticles (MNPs) as heterogeneous
support, which can be easily removed from the reaction mixture by magnetic
separation [14–18].
It is well known that boron compounds are very potent Lewis acids due to the
electron deficiency of the boron core. There are many reports about the application
of various catalytic systems based on boron compounds [19].
Between them, BF3 is a potent and common material with a high-level Lewis
acid property that is used as a Lewis acid catalyst in isomerization, alkylation,
esterification, condensation, Mukaiyama aldol addition, and many other reactions
[20]. Though BF3 is a strong catalyst in many organic transformations, it is not a
recoverable material and its application produces hazardous toxic waste. So,
introducing of some appropriate methods to make this material a separable catalytic
system is of great interest in Lewis acid-catalyzed organic synthesis. One useful
way to attain this goal is connection of BF3 on a heterogeneous support.
The addition of a cyanide anion to imines (the Strecker reaction) [21] provides
one of the most important and straightforward methods for the synthesis of a-
aminonitriles, which are useful intermediates for the synthesis of amino acids [22,
23] and nitrogen-containing heterocycles [24, 25], and other biologically useful
molecules such as saframycin A, or phthalascidi [26]. Several modifications of the
Strecker reaction have been reported, using a variety of cyanide reagents, such as
alkaline cyanides [21, 27, 28], diethylphosphoro cyanidate [29], Bu3SnCN [30] and
Et2AlCN [31], as well as catalysts such as InCl3 [32], BiCl3 [33], montmorillonite
KSF clay [34], silica-based scandium(III) [35], SO42-/ZrO2 [36], ferric perchlorate
[37], Fe(Cp)2PF6 [38], InI3 [39], I2 [40], K5CoW12O40.3WATER [41], vanadyl
triflate [42], Fe3O4 [43], guanidine hydrochloride [44], xanthan sulfuric acid [45],
[Bmim]BF4 [46], silica sulfuric acid [47], hydrophobic sulfonic acid based
nanoreactors [48] and silica-bonded S-sulfonic acid [49] under various reaction
conditions. However, many of these methods suffer from some drawbacks such as
the use of stoichiometric reagents and hazardous and often expensive catalysts, low
yields of products, harsh reaction conditions, extended reaction times, tedious
catalyst preparation procedures, the use of volatile and hazardous organic solvents,
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Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
non-compliance with ‘‘green’’ chemistry protocols and also require tedious workup
leading to the generation of a large amount of toxic waste. Furthermore, many of
these catalysts are deactivated or sometimes decomposed by amines and water that
exist during imine formation. Also, it has been shown that trimethylsilyl cyanide
(TMSCN) is a very effective, relatively safe and easy-to-handle cyanide source for
this purpose [50–57]. Consequently, development of a general, efficient, inexpen-
sive and environmentally benign method for the synthesis of a-aminonitriles is still
in demand.
As a part of our continuing studies in developing efficient heterogeneous
catalysts [58–60], we found that synthesis of a-aminonitriles via a one-pot three-
component reaction can be efficiently achieved in the presence of Fe3O4 magnetic
nanoparticles supported-boron trifluoride (BF3–Fe3O4 MNPs) as a new magnetically
separable heterogeneous Lewis acid catalyst in ethanol under ultrasonic irradiation
at room temperature.
Experimental
Apparatus and analysis
Reagents and solvents were purchased from Merck, Fluka or Aldrich. Melting points
were determined in capillary tubes in an electro-thermal C14250 apparatus. The
progress of the reaction and the purity of compounds were monitored by thin layer
chromatography (TLC) analytical silica gel plates (Merck 60 F250). All known
compounds were identified by comparison of their melting points and proton nuclear
magnetic resonance (1H NMR) data with those in the authentic samples. The 1H NMR
(250 MHz) and Carbon 13 NMR (13C NMR, 62.5 MHz) were run on a Bruker
Avance DPX-250, Fourier transform (FT)-NMR spectrometer. Chemical shifts are
given as d values against tetramethylsilane (TMS) as the internal standard and
J values are given in Hz. The elemental analysis was performed on a Perkin-Elmer
240-B microanalyzer. The ultrasound apparatus was a cleaning bath Wiseclear
770 W (Seoul, Korea). The operating frequency was 40 kHz and the output power
was 200 W, estimated calorimetrically. The reaction flasks were located in the
maximum energy area in the water bath, where the surface of the reactants (reaction
vessel) is slightly lower than the level of the water, and the addition or removal of
water controlled the temperature of the water bath. The temperature of the water bath
was controlled at 25–30 °C. Moreover, the temperature of the reaction flask was
monitored with an internal thermometer and it was stable between 36 and 40 °C
during the progress of all reactions. All experiments performed in this work were
repeated three times. The yield reported represents the average of the values obtained
for each reaction. The X-ray diffraction (XRD) patterns were recorded on a Bruker
D8 ADVANCE X-ray diffractometer using nickel-filtered Cu Ka radiation
˚
(k = 1.5406 A). Scanning electron micrograms were obtained using
a
KYKY-EM3200 instrument. Potentiometric data was collected using a pH/mV
meter, AZ model 86502-pH/ORP. The inductively coupled plasma (ICP) analysis
was determined using an ICP analyzer (Varian, Vista-Pro). F3O4 magnetic
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M. Shekouhy et al.
nanoparticles were synthesized using a reported method [61]. The fluoride content of
catalysts was determined based on a reported method [62].
Synthesis of 4-(3-bromopropoxy)benzaldehyde (9)
A mixture of p-hydroxybenzaldehyde (0.02 mol, 2.44 g), 1,3-dibromopropane
(0.06 mol), K2CO3 (2.76 g, 0.02 mol) and tetrabutyl ammonium bromide (TBAB,
0.1 g) in acetonitrile (50 mL) was refluxed in a double-necked round-bottom flask
(100 mL) equipped with a condenser for 10 h. After this time, the reaction mixture
was cooled and the solvent was evaporated under reduced pressure and the resulting
foam was dissolved in chloroform (150 mL) and washed with water (3 9 150 mL).
The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude
product was purified by column chromatography on silica gel [eluting with a
mixture of n-hexane and ethyl acetate (1:2), Rf = 0.6], giving the desired product as
a white solid in 80 % yield (3.9 g).
Synthesis of 4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-
propoxy)benzaldehyde (1b)
To a double-necked 250-mL round-bottom flask equipped with a condenser
containing an appropriate amount of presilylated adenine (0.01 mol, 2.79 g) and
4-(3-bromopropoxy)benzaldehyde (9) (0.01 mol, 2.41 g) diluted in freshly distilled,
anhydrous tetrahydrofurane (100 mL), anhydrous tetrabutyl ammonium fluoride
(TBAF, 2.62 g, 0.01 mol) in dried tetrahydrofurane (20 mL) was gradually added
over 20 min. (For the production of presilylated adenine, please see Ref. [63]).
Then, the mixture was heated at reflux temperature and the progress of the reaction
was monitored by TLC. After reaction completion, the solvent was evaporated at
reduced pressure and the residue was dissolved in chloroform (200 mL) and washed
with water (3–100 mL). The organic layer was dried over Na2SO4 and concentrated
to afford the crude product. The crude product was purified by column
chromatography on silica gel [eluting with a mixture of n-hexane and ethyl acetate
(1:2), Rf = 0.6], giving the desired product as a white solid in 78 % yield (2.31 g).
General procedure for the synthesis of a-aminonitriles
Aldehyde or ketone (1 mmol) and amine (1.2 mmol) were added to a mixture of
Fe3O4–BF3 (50 mg) and ethanol (5 mL) in a 25-mL Pyrex flask and the resulting
mixture was continuously irradiated for 2 min. TMSCN (1.2 mmol) was added and
the resulting mixture was continuously irradiated for the appropriate time (Table 2)
at room temperature. The reactions were followed by TLC using n-hexane/ethyl
acetate (3:1) as an eluent. The ultrasonic apparatus used, showed the temperature
automatically so the temperature was controlled and fixed at room temperature by
pouring cold water in the bath in the case of any elevation of temperature. After
completion of the reaction, heterogeneous magnetic particles of the catalyst were
separated with a magnet, washed with ethanol (5 mL), dried under reduced pressure
for 24 h at 100 °C and kept for the next use. After catalyst isolation, water (20 mL)
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Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
was added and stirred magnetically for 5 min. Insoluble crude products were filtered
and recrystallized from ethanol/water (4:1). In the case of oil products, appropriate
amounts of ethyl acetate (5 mL, two times) were added; the organic layer was
washed with brine (5 mL), dried (MgSO4), and concentrated. The residue was
chromatographed over silica gel (15-% ethyl acetate in hexane) to give a pure
product.
Selected spectral data
2-(Butylamino)-2-(pyridin-3-yl)acetonitrile (Compound 4aw)
Colorless oil [65], tmax (KBr): 3345, 3025, 2962, 2220 cm-1. 1H NMR [250 MHz,
deuterated chloroform (CDCl3)]: d (ppm) 0.91 (t, J = 7.9 Hz, 3H), 1.20–1.38 (m,
2H), 1.46–1.60 (m, 2H), 3.08 (q, J = 7.5 Hz, 2H), 3.91–4.22 (m, 2H), 7.45 (d,
J = 8.0 Hz, 1H), 7.83 (dd, J = 2.0, 8.0 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.85 (s,
1H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 13.9, 20.1, 32.3, 45.8, 49.0, 116.9,
123.0, 132.4, 134.0, 147.5, 150.3. Anal. Calcd for C11H15N3: C, 69.81; H, 7.99; N,
22.20 %; found: C, 69.88; H, 7.81; N, 22.12 %.
2-(Phenylamino)hexanenitrile (Compound 4az)
White crystalline solid, mp: 58–59 °C (55–57 °C) [25] tmax (KBr): 3352, 3015,
1
2945, 2230 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 0.95 (t, J = 7.5 Hz, 3H),
1.20–1.48 (m, 2H), 1.55–1.67 (m, 2H), 3.10 (q, J = 7.5 Hz, 2H), 3.95–4.25 (m,
2H), 6.92–7.29 (m, 5H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 14.2, 22.1, 25.4,
31.5, 48.7, 113.0, 116.1, 117.6, 129.2, 147.9. Anal. Calcd for C12H16N2: C, 76.55;
H, 8.57; N, 14.88 %; found: C, 76.54; H, 8.50; N, 14.83 %.
2-(Benzylamino)-3-methylbutanenitrile (Compound 4ba)
Colorless oil (colorless oil) [25], tmax (KBr): 3355, 3015, 2952, 2220 cm-1. 1H NMR
(250 MHz, CDCl3): d (ppm) 1.03 (d, J = 7.5 Hz, 3H), 1.08 (d, J = 7.5 Hz, 3H), 1.52
(brs, 1H), 1.93 (m, 1H), 2.05–2.16 (distorted AB System, 2H), 3.27 (d, J = 7.5 Hz,
1H), 3.85 (d, J = 12.8 Hz, 1H,), 4.11 (d, J = 12.8 Hz, 1H), 7.24–7.44 (m, 5H).
13C NMR (62.5 MHz, CDCl3): d (ppm) 18.2, 19.6, 31.7, 51.5, 56.5, 119.0, 127.1,
128.2, 128.9, 138.8. Anal. Calcd for C12H16N2: C, 76.55; H, 8.57; N, 14.88 %; Found:
C, 76.45; H, 8.51; N, 14.72 %.
1-(Phenylamino)cyclopentanecarbonitrile (Compound 4be)
White crystalline solid, mp: 54–57 °C (55–56) [65], tmax (KBr): 3348, 3025, 2950,
2230 cm-1. 1H NMR (250 MHz, CDCl3): d (ppm) 1.40 (m, 2H), 1.55 (m, 2H), 1.88
(m, 2H), 2.12 (m, 2H), 3.98 (brs, 1H), 6.68 (d, J = 7.5 Hz, 2H,), 6.95 (t,
J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3): d (ppm)
22.8, 33.9, 53.0, 113.8, 117.2, 119.8, 131.2, 143.8. Anal. Calcd for C12H14N2: C,
77.38; H, 7.58; N, 15.04 %; Found: C, 77.25; H, 7.55; N, 14.99 %.
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M. Shekouhy et al.
1-(p-Tolylamino)cyclopentanecarbonitrile (Compound 4bf)
White crystalline solid, mp: 55–57 °C (57–59) [65], tmax (KBr): 3352, 3020, 2935,
2230 cm-1. 1H NMR (250 MHz, CDCl3): d (ppm) 1.45 (m, 2H), 1.55 (m, 2H), 1.87
(m, 2H), 2.10 (m, 2H), 2.31 (s, 3H), 3.97 (brs, 1H), 6.88 (d, J = 7.8 Hz, 2H,), 6.96
(d, J = 7.8 Hz, 2H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 22.5, 24.2, 32.7, 51.4,
113.0, 119.5, 126.4, 128.8, 143.5. Anal. Calcd for C13H16N2: C, 77.96; H, 8.05; N,
13.99 %; Found: C, 77.90; H, 8.06; N, 13.92 %.
1-(Phenylamino)cycloheptanecarbonitrile (Compound 4bg)
White crystalline solid, mp: 55–57 °C (56–57) [65], tmax (KBr): 3350, 3030, 2925,
1
2220 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 1.25 (brs, 4H), 1.36 (brs, 4H),
1.70 (brs, 4H), 4.05 (s, 1H), 6.65 (d, J = 8.0 Hz, 2H), 6.85 (t, J = 8.0 Hz, 1H,),
7.05 (t, J = 8.0 Hz, 2H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 21.1, 27.9, 33.5,
52.0, 113.5, 117.7, 119.0, 127.5, 143.5. Anal. Calcd for C14H18N2: C, 78.46; H,
8.47; N, 13.07 %; Found: C, 78.33; H, 8.41; N, 13.12 %.
1-(4-Bromophenylamino)cycloheptanecarbonitrile (Compound 4bh)
White crystalline solid, mp: 60–63 °C (62–64) [65], tmax (KBr): 3405, 3025, 2930,
1
2230 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 1.21 (brs, 4H), 1.35 (brs, 4H),
1.73 (brs, 4H), 4.02 (s, 1H), 6.87 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H,).
13C NMR (62.5 MHz, CDCl3): d (ppm) 21.0, 27.6, 33.2, 51.8, 113.2, 115.4, 120.1,
133.8, 143.9. Anal. Calcd for C14H17BrN2: C, 57.35; H, 5.84; N, 9.55 %; Found: C,
57.32; H, 5.72; N, 9.62 %.
2-Phenyl-2-(phenylamino)propanenitrile (Compound 4bi)
White crystalline solid, mp: 142–144 °C (143–145) [65], tmax (KBr): 3320, 3046,
1
2225 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 1.95 (s, 3H), 4.52 (brs, 1H),
6.75–6.88 (m, 3H), 7.25–7.38 (m, 5H), 7.40 (d, J = 8.5 Hz, 2H). 13C NMR
(62.5 MHz, CDCl3): d (ppm) 22.8, 66.5, 113.9, 120.1, 120.9, 127.6, 128.1, 128.8,
129.0, 130.1, 147.8. Anal. Calcd for C15H14N2: C, 81.05; H, 6.35; N, 12.60 %;
Found: C, 80.91; H, 6.33; N, 12.72 %.
2-(4-Bromophenylamino)-2-p-tolylpropanenitrile (Compound 4bj)
White crystalline solid, mp: 180–182 °C (179–181) [65], tmax (KBr): 3338, 3075,
2950, 2308 cm-1. 1H NMR (250 MHz, CDCl3): d (ppm) 1.94 (s, 3H), 2.35 (s, 3H),
4.29 (brs, 1H), 6.65 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.25–7.39 (m,
4H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 21.8, 23.5, 68.4, 114.2, 115.8, 120.0,
127.0, 128.2, 128.7, 132.3, 137.7, 146.9. Anal. Calcd for C16H15BrN2: C, 60.97; H,
4.80; N, 8.89 %; Found: C, 61.02; H, 4.88; N, 8.95 %.
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Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
2-(Isopropylamino)-2-(3-nitrophenyl)propanenitrile (Compound 4bk)
Yellow crystalline solid, mp: 118–119 °C (115–117) [65], tmax (KBr): 3360, 3050,
2950, 2228 cm-1. 1H NMR (250 MHz, CDCl3): d (ppm) 1.05 (d, J = 7.8 Hz, 6H),
1.72 (brs, 1H), 1.91 (s, 3H), 2.80 (m, 1H), 7.69–7.75 (m, 2H), 8.09 (d, J = 8.5 Hz,
1H), 8.23 (d, J = 2.0 Hz, 1H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 23.4, 24.8,
46.0, 63.1, 119.5, 123.5, 62.5.0, 127.6, 131.8, 134.5, 147.0. Anal. Calcd for
C12H15N3O2: C, 61.79; H, 6.48; N, 18.01 %; Found: C, 61.88; H, 6.45; N, 17.89 %.
2-(Benzylamino)-2,2-diphenylacetonitrile (Compound 4bk)
White crystalline solid, mp: 155–158 °C (155–157) [65], tmax (KBr): 3355, 3060,
2225 cm-1. 1H NMR (250 MHz, CDCl3): d (ppm) 2.00–2.09 (distorted AB System,
2H), 1.90 (s, 1H), 7.23–7.35 (m, 15H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 46.6,
68.5, 114.0, 126.9, 127.5, 127.9, 128.0, 128.5, 129.2, 140.9, 143.6. Anal. Calcd for
C21H18N2: C, 84.53; H, 6.08; N, 9.39 %; Found: C, 84.56; H, 6.17; N, 9.32 %.
2-(4-Bromophenylamino)-2,2-diphenylacetonitrile (Compound 4bm)
White crystalline solid, mp: 173–175 °C (171–173) [65], tmax (KBr): 3360, 3045,
2230 cm-1 1H NMR (250 MHz, CDCl3): d (ppm) 4.60 (brs, 1H), 6.50 (d,
.
J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.21–7.35 (m, 10H). 13C NMR
(62.5 MHz, CDCl3): d (ppm) 68.5, 114.0, 114.6, 115.8, 126.2, 128.0, 129.5, 132.7,
143.5, 147.2. Anal. Calcd for C20H15BrN2: C, 66.13; H, 4.16; N, 7.71 %; Found: C,
66.19; H, 4.23; N, 7.83 %.
3-Oxo-3-phenyl-2-(phenylamino)propanenitrile (Compound 4bn)
White crystalline solid, mp: 62–64 °C (59–61) [65], tmax (KBr): 3460, 3010, 2950,
2230, 1695 cm-1. 1H NMR (250 MHz, CDCl3): d (ppm) 4.20 (brs, 1H), 5.05 (s, 1),
6.40 (d, J = 8.0 Hz, 2H), 6.63 (t, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 2H), 7.45 (t,
J = 7.5 Hz, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.81 (d, J = 7.5 Hz, 2H). 13C NMR
(62.5 MHz, CDCl3): d (ppm) 63.0, 113.0, 116.7, 126.5, 126.9, 128.0, 129.9, 133.2,
135.0, 143.8, 197.3. Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86 %;
Found: C, 76.20; H, 5.02; N, 11.94 %.
2-(p-Tolylamino)-3-oxo-3-phenylpropanenitrile (Compound 4bo)
White crystalline solid, mp: 65–68 °C (63–65) [65], tmax (KBr): 3405, 3020, 2938,
1
2230, 1690 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 1.95 (s, 3H), 4.00 (brs,
1H), 5.19 (s, 1), 6.50 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 7.44 (t,
J = 8.0 Hz, 2H), 7.62 (t, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H). 13C NMR
(62.5 MHz, CDCl3): d (ppm) 24.5, 62.5, 113.4, 116.0, 126.90, 126.98, 128.0, 129.1,
133.0, 135.5, 143.4, 197.0. Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N,
11.19 %; Found: C, 76.62; H, 5.71; N, 11.01 %.
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1,2,3,4-Tetrahydro-1-(phenylamino)naphthalene-1-carbonitrile (Compound 4 bp)
White crystalline solid, mp: 120–121 °C (123–62.5) [65], tmax (KBr): 3360, 3045,
2940, 2230 cm-1 1H NMR (250 MHz, CDCl3): d (ppm) 1.55–1.70 (m, 2H),
.
2.08–2.23 (m, 2H), 2.88–2.95 (m, 2H), 4.60 (brs, 1H), 6.80–6.89 (m, 7H), 7.20 (t,
J = 8.0 Hz, 2H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 14.8, 29.5, 38.5, 63.0,
113.0, 120.9, 121.0, 62.5.5, 127.3, 129.9, 134.0, 135.7, 147.0. Anal. Calcd for
C17H16N2: C, 82.22; H, 6.49; N, 11.28 %; Found: C, 82.12; H, 6.40; N, 11.33 %.
2-Oxo-3-(phenylamino)indoline-3-carbonitrile (Compound 7aa)
White crystalline solid, mp: 94–95 °C (91–92) [65], tmax (KBr): 3390, 3300, 3040,
2960, 2235, 1668 cm-1. 1H NMR (250 MHz, CDCl3): d (ppm) 4.88 (brs, 1H), 6.85
(d, J = 7.5 Hz, 1H), 7.32–7.68 (m, 8H), 8.30 (s, 1H). 13C NMR (62.5 MHz,
CDCl3): d (ppm) 71.0, 111.3, 119.8, 121.0, 62.5.3, 126.7, 129.0, 131.3, 132.8,
140.5, 148.9, 152.9, 171.0. Anal. Calcd for C15H11N3O: C, 72.28; H, 4.45; N,
16.86 %; Found: C, 72.10; H, 4.52; N, 16.95 %.
3-(p-Tolylamino)-2-oxoindoline-3-carbonitrile (Compound 7ab)
White crystalline solid, mp: 103–105 °C (99–101) [65], tmax (KBr): 3400, 3298,
1
3035, 2960, 2230, 1670 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 2.15 (s, 3H),
4.95 (brs, 1H), 6.98 (d, J = 7.5 Hz, 1H), 7.28–7.51 (m, 7H), 8.68 (brs, 1H,).
13C NMR (62.5 MHz, CDCl3): d (ppm) 24.2, 71.5, 111.8, 119.0, 122.5, 62.5.4,
126.8, 129.0, 131.7, 132.4, 140.0, 148.8, 152.3, 171.2. Anal. Calcd for C16H13N3O:
C, 72.99; H, 4.98; N, 15.96 %; Found: C, 72.86; H, 4.86; N, 15.89 %.
5-Methyl-2-oxo-3-(phenylamino)indoline-3-carbonitrile (Compound 7ac)
White crystalline solid, mp: 109–111 °C (110–112) [65], tmax (KBr): 3400, 3330,
1
3050, 2970, 2230, 1670 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 2.20 (s, 3H),
5.05 (brs, 1H), 6.75 (s, 1H), 6.91–7.08 (brs, 2H), 7.99 (m, 5H), 9.95 (brs, 1H).
13C NMR (62.5 MHz, CDCl3): d (ppm) 21.6, 71.5, 111.5, 119.0, 121.5, 62.5.4,
62.5.9, 126.0, 129.4, 131.8, 131.9, 132.9, 140.8, 171.0. Anal. Calcd for C16H13N3O:
C, 72.99; H, 4.98; N, 15.96 %; Found: C, 72.91; H, 4.95; N, 16.01 %.
3-(4-Bromophenylamino)-5-methyl-2-oxoindoline-3-carbonitrile (compound 7ad)
White crystalline solid, mp: 117–119 °C (119–121) [65], tmax (KBr): 3410, 3300,
1
3030, 2980, 2220, 1670 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 2.20 (s, 3H),
5.05 (brs, 1H), 6.74 (s, 1H), 6.99–7.08 (brs, 2H), 7.98–8.28 (m, 4H), 9.83 (brs, 1H).
13C NMR (62.5 MHz, CDCl3): d (ppm) 22.5, 71.3, 111.8, 119.0, 122.0, 62.5.7,
62.5.8, 126.5, 129.3, 131.0, 131.9, 132.0, 140.5, 171.0. Anal. Calcd for C16H12-
BrN3O: C, 56.16; H, 3.53; N, 12.28 %; Found: C, 56.02; H, 3.59; N, 12.39 %.
123

Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
1,2-Dihydro-2-oxo-1-(phenylamino)acenaphthylene-1-carbonitrile (Compound 7ae)
Pale yellow crystalline solid, mp: 137–138 °C (135–137) [65], tmax (KBr): 3465,
3050, 2980, 2220, 1695 cm-1. 1H NMR (250 MHz, CDCl3): d (ppm) 5.07 (brs, 1H),
7.44 (t, J = 7.5 Hz, 1H), 7.48–7.60 (m, 5H), 7.60 (d, J = 7.5 Hz, 1H), 7.82 (t,
J = 7.5 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 8.28 (d,
J = 8.0 Hz, 1H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 73.0, 120.5, 121.1, 123.0,
126.2, 127.0, 128.5, 129.0, 129.4, 130.8, 131.1, 131.3, 132.5, 133.2, 134.6, 142.1,
196.2. Anal. Calcd for C19H12N2O: C, 80.27; H, 4.25; N, 9.85 %; Found: C, 80.19;
H, 4.20; N, 9.76 %.
1-(p-Tolylamino)-1,2-dihydro-2-oxoacenaphthylene-1-carbonitrile (Compound 7af)
Pale yellow crystalline, mp: 139–142 °C (138–140) [65], tmax (KBr): 3490, 3030,
1
2960, 2220, 1695 cm-1. H NMR (250 MHz, CDCl3): d (ppm) 2.20 (s, 3H), 5.00
(brs, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.49–7.63 (m, 4H), 7.72 (d, J = 7.5 Hz, 1H),
7.79 (t, J = 7.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 8.21
(d, J = 8.0 Hz, 1H). 13C NMR (62.5 MHz, CDCl3): d (ppm) 22.6, 72.3, 120.5,
121.8, 123.6, 126.3, 127.0, 128.8, 129.0, 129.4, 130.2, 131.5, 131.6, 132.0, 133.2,
134.5, 142.4, 196.0. Anal. Calcd for C20H14N2O: C, 80.52; H, 4.73; N, 9.39 %;
Found: C, 80.48; H, 4.62; N, 9.47 %.
1-(4-Bromophenylamino)-1,2-dihydro-2-oxoacenaphthylene-1-carbonitrile
Compound 7ag)
Pale yellow crystalline, mp: 170–173 °C (168–170) [65], tmax (KBr): 3980, 3030,
2970, 2230, 1710 cm-1 1H NMR (250 MHz, CDCl3): d (ppm) 5.15 (s, 1H),
.
7.40–7.49 (m, 2H,), 7.50–7.59 (m, 2H,), 7.66 (d, J = 7.5 Hz, 1H), 7.82 (d,
J = 8.5 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.19 (d,
J = 7.5 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H). 13C NMR (62.5 MHz, CDCl3): d (ppm)
71.6, 120.2, 121.3, 123.0, 127.4, 128.5, 129.0, 129.5, 130.3, 130.8, 131.5, 133.0,
134.5, 135.9, 142.8, 148.2, 196.0. Anal. Calcd for C19H11BrN2O: C, 62.83; H, 3.05;
N, 7.71 %; Found: C, 62.71; H, 3.01; N, 7.89 %.
2-(4-(3-(6-Amino-9H-purin-9-yl)propoxy)phenyl)-2-(phenylamino)acetonitrile
(Compound 11)
White crystalline, mp: 234–237 °C. tmax (KBr): 3370,2890, 2330, 1670, 1650,
1610, cm-1 1H NMR (250 MHz, CDCl3): d (ppm) 2.07 (m, 2H), 3.63 (t,
.
J = 7.0 Hz, 2H), 4.16 (t, J = 7.0 Hz, 2H), 5.31 (s, 1H), 6.23 (br, 2H), 6.39 (s, 1H),
6.86 (t, J = 7.5 Hz, 1H), 7.02- 7.13 (m, 6H), 7.59 (t, J = 7.5 Hz, 2H), 8.17 (s, 1H).
13C NMR (62.5 MHz, CDCl3): d (ppm) 29.1, 41.7, 49.7, 69.1, 114.8, 116.2, 118.5,
119.3, 119.8, 128.6, 128.8, 130.3, 143.4, 145.7, 150.9, 152.3, 155.7, 157.9. Anal.
Calcd for C19H11BrN2O: C, 66.15; H, 5.30; N, 24.55 %; Found: C, 66.21; H, 5.38;
N, 24.48 %. MS: m/z 399.18.
123

M. Shekouhy et al.
Results and discussions
In the first step, Fe3O4–BF3 magnetic nanoparticles were prepared by stirring a
mixture of Fe3O4 magnetic nanoparticles and BF3.Et2O in toluene and calcination of
obtained solid in 450 °C. The scanning electron microscopy (SEM) image of
synthesized Fe3O4–BF3 magnetic nanoparticles (Fig. 1) shows that the catalyst
particles possess near-spherical morphology with relatively good monodispersity. In
this study, the average diameter of magnetic nanoparticles was estimated to be
*50 nm.
The XRD pattern of magnetic nanoparticles is shown in Fig. 2. Both Fe3O4 and
Fe3O4–BF3 magnetic nanoparticles show diffraction peaks at 2h = 30.3, 35.6, 43.3,
53.8, 57.4 and 62.9 that are indexed to the crystalline cubic inverse spinel structure
of Fe3O4 nanoparticles.
Figure 3 shows the infrared (IR) spectra of Fe3O4 magnetic nanoparticles and
synthesized Fe3O4–BF3 magnetic nanoparticles at different calcination temperatures
over the 400–2000 cm-1 region. As shown in Fig. 3, all samples show characteristic
peaks at 560 and 638 cm-1, which are assigned to Fe–O stretching modes. The peak
at 1083 is assigned to C–O (the residue of ether) that is not observed in the calcined
samples. Apart from the main peaks of magnetic nanoparticles, there is a wide peak
at *1400 cm-1, which is assigned to B–O stretching.
Moreover the loading level of boron on the surface of F3O4 magnetic
nanoparticles was estimated to be about 0.537 mmol g-1 as determined via the
ICP method. To determine the bonding state of BF3 and B/F mole ratios on the
Fe3O4–BF3 magnetic nanoparticles before and after heat treatment, the fluoride
contents of freshly synthesized Fe3O4–BF3 magnetic nanoparticles and calcinated
Fe3O4–BF3 magnetic nanoparticles at 450 °C were measured by a potentiometric
method using a fluoride ion-selective electrode. Using this method, the B/F mole
ratios for freshly synthesized Fe3O4–BF3 magnetic nanoparticles and calcinated
Fig. 1 The scanning electron microscopy (SEM) image of Fe3O4–BF3 magnetic nanoparticles
123

Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
Fig. 2 The XRD pattern of Fe3O4 magnetic nanoparticles (a) and Fe3O4–BF3 magnetic nanoparticles (b)
Fig. 3 FT-IR spectra of Fe3O4
magnetic nanoparticles (a),
Fe3O4–BF3 magnetic
a)
nanoparticles before calcination
(b), Fe3O4–BF3 magnetic
nanoparticles after calcination at
350 °C (c), Fe3O4–BF3
b)
magnetic nanoparticles after
calcination at 400 °C (d) and
Fe3O4–BF3 magnetic
c)
nanoparticles after calcination at
450 °C (e)
d)
e)
2000
1600
1200
800
400
Wavenumber (cm-1)
Fe3O4–BF3 magnetic nanoparticles at 450 °C were obtained as 1/2.94 & 1/3 and
1/1.93 & 1/2, respectively. These results confirm the presence of BF3 on the
surface of freshly synthesized Fe3O4–BF3 magnetic nanoparticles with bonding
123

M. Shekouhy et al.
interaction between the oxygen of Fe3O4 magnetic nanoparticles and the boron of
BF3. The B/F mole ratio of 1/2 in calcinated Fe3O4–BF3 magnetic nanoparticles also
confirms the presence of a covalent bond between the oxygen of Fe–O and boron
and formation of –O–BF2 due to evolution of hydrofluoric acid (HF) during the
calcination. Thus, Fe–O–BF2 is the final structural form of the catalyst in calcinated
Fe3O4–BF3 magnetic nanoparticles.
The catalyst acidity characters, including the acidic strength and the total number
of acid sites were determined by a potentiometric titration. According to this
method, the initial electrode potential (Ei) indicates the maximum acid strength of
the surface sites and the range of where a plateau is reached (mili-equivalents of
used n-butylamine per gram of the catalyst) indicates the total number of acid sites
[64]. Therefore, a suspension of the catalyst in acetonitrile was potentiometrically
titrated with a solution of 0.02-molar n-butylamine and obtained results are
summarized in Fig. 4. As shown in Fig. 4, Fe3O4–BF3 magnetic nanoparticles
display higher strength than the Fe3O4 magnetic nanoparticles.
Moreover, magnetization properties of Fe3O4 magnetic nanoparticles and
Fe3O4–BF3 magnetic nanoparticles were investigated using the vibrating sample
magnometer (VSM) and obtained results are shown in Fig. 5. Based on these
results, the saturation magnetization value was measured to be 60 emu g-1 for
Fe3O4 magnetic nanoparticles and 50 emu g-1 for Fe3O4–BF3 magnetic nanopar-
ticles. The results show that in this case, surface modification has an insignificant
effect on the magnetic properties of Fe3O4 magnetic nanoparticles.
Fig. 4 Potentiometric titration
400
of (a) Fe3O4 magnetic
nanoparticles and
(b) Fe3O4–BF3 magnetic
nanoparticles
200
0
a)
-200
-400
-600
-800
b)
0.0
0.2
0.4
meq/g
0.6
0.8
1.0
123

Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
60
40
20
0
Fig. 5 The magnetisation
behaviour of Fe3O4 magnetic
nanoparticles and Fe3O4–BF3
magnetic nanoparticles
Fe3O4
Fe3O4-BF3
-20
-40
-60
-8000
-4000
0
4000
8000
Applied field (Oe)
In the next step, to introduce the applicability of Fe3O4–BF3 magnetic
nanoparticles as a new magnetically separable Lewis acid, its efficiency was
explored in a three-component reaction of carbonyl compounds with amines and
TMSCN under ultrasonic irradiation (Scheme 1).
To find an appropriate reaction medium for the synthesis of titled compounds in
the presence of Fe3O4–BF3 magnetic nanoparticles, the one-pot three-component
condensation of benzaldehyde (1 mmol), aniline (1.2 mmol) and trimethylsilyl
cyanide (1.2 mmol) was selected as a model reaction and was examined in several
reaction mediums; the yield and reaction times were monitored in the presence of
ultrasonic irradiation at room temperature and obtained results are summarized in
Table 1.
R1
O
R2
25
Fe3O4-BF3 MNPs
Ethanol
R1
CN
(1)
R3 NH2
R2 HN R3
(2)
H3C
Sonication )))))))
r.t.
CH3
(4aa-bp)
3-50 min 79-96%
Si
H3C
CN
(3)
Scheme 1 The ultrasound-promoted one-pot three-component synthesis of a-aminonitriles using
Fe3O4–BF3 magnetic nanoparticles as a new magnetically separable Lewis acid catalyst
123

M. Shekouhy et al.
As it is clear from Table 1, the best results were obtained in the presence of only
50 milligrams of Fe3O4–BF3 magnetic nanoparticles in ethanol as a solvent
(Table 1, entry 6). However, the increasing amount of Fe3O4–BF3 magnetic
nanoparticles does not affect the reaction yield and time (Table 1, entry 8), but the
reaction yield was decreased in the presence of lower amount of Fe3O4–BF3
magnetic nanoparticles (Table 2, entry 7). Moreover, the model reaction was
investigated in the absence of a catalyst and the reaction did not proceed even after a
long time of ultrasonic irradiation (Table 1, entry 9). In another study, the model
reaction was investigated in the presence of Fe3O4 magnetic nanoparticles (50 mg)
and the reaction did not proceed even after a long time of ultrasonic irradiation.
These observations establish the crucial role of Fe3O4–BF3 magnetic nanoparticles
as a Lewis acid catalyst.
More recently, we introduced sulfuric acid-modified PEG-6000 (PEG-OSO3H) as
¨
an efficient Bronsted acid-surfactant combined catalyst for the synthesis of a-
aminonitriles and very good results were obtained [62]. So, in order to examine the
scope and efficiency of Fe3O4–BF3 magnetic nanoparticles as a new heterogeneous
magnetically separable Lewis acid catalyst, production of all previously synthesized
a-aminonitriles (that were synthesized in the presence of PEG-SO3H) was explored
under the optimized conditions. For this purpose, a broad range of structurally diverse
aldehydes (aliphatic and aromatic) as well as ketones and amines (aliphatic or
aromatic) were condensed with trimethylsilyl cyanide and results are displayed in
Table 2. As can be seen from Table 2, all reactions proceeded efficiently and desired
products were obtained in good to excellent yields in relatively short reaction times
without formation of any byproducts. Aromatic aldehydes having electron-with-
drawing groups (Table 2, entries 4an, 4ao and 4at) reacted at faster rates compared
with those that substituted with electron-releasing groups (Table 2, entries 4aq, 4ar
and 4as). Besides, the presented method has been successfully used for heteroaromatic
aldehydes as acid- and base-sensitive compounds and corresponding a-aminonitriles
were obtained in excellent yields without any byproducts (Table 2, entries 4au, 4av
Table 1 The three-component reaction between benzaldehyde (1 mmol), aniline (1.2 mmol) and
trimethylsilyl cyanide (1.2 mmol) in several reaction mediums under ultrasonic irradiation at room
temperature in the presence of Fe3O4–BF3 magnetic nanoparticles
Entry
Solvent (5 mL)
Catalyst (mg)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
a
Dichloromethane
Chloroform
Ethyl acetate
Methanol
Water
50
50
50
50
50
50
40
70
–
60
60
60
10
35
5
Trace
25
49
93
81
Ethanol
94
Ethanol
20
5
87
Ethanol
94
Ethanol
60
No reaction
Isolated yield
123

Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
Table 2 Ultrasound-assisted synthesis of a-aminonitriles using Fe3O4–BF3
Entry
R1
R2
Time
(min)
Yield
(%)a
4aa
4ab
4ac
4ad
4ae
4af
C6H5
C6H5
5
7
90
90
89
90
87
88
85
85
88
90
84
91
90
89
90
88
85
81
86
92
91
89
81
89
83
81
81
79
C6H5
3,4-CH3-C6H3
4-Br-C6H4
4-CH3-C6H4
–CH2CH2OCH2CH2–
C6H5-CH2
CH3CH2CH2CH2
(CH3)2CH
–CH2CH2CH2CH2–
4-Cl-C6H4
1-Naphthyl
4-CH3-C6H4
C6H5
C6H5
5
C6H5
5
C6H5
25
30
35
30
30
8
C6H5
4ag
4ah
4ai
C6H5
C6H5
C6H5
4aj
C6H5
4ak
4al
C6H5
25
5
4-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
4-F-C6H4
2,4-Cl-C6H3
4-OCH3-C6H4
3-OCH3-C6H4
3-OCH3-C6H4
3-NO2-C6H4
2-Thienyl
2-Furyl
4am
4an
4ao
4ap
4aq
4ar
5
C6H5
6
4-CH3-C6H4
4-CH3-C6H4
C6H5
6
20
25
30
30
3
CH3CH2CH2CH2
C6H5
4as
4at
C6H5
4au
4av
4aw
4ax
4ay
4az
4ba
4bb
C6H5-CH2
C6H5-CH2
CH3CH2CH2CH2
C6H5
15
15
35
15
25
20
25
30
3-Pyridyl
4-CH3-C6H4
1-Naphthyl
CH3CH2CH2CH2
(CH3)2CH
(CH3)2CH
C6H5
C6H5
C6H5-CH2
–CH2CH2CH2CH2–
Reaction condition: aldehyde or ketone (1 mmol), amine (1.2 mmol), trimethylsilyl cyanide (1.2 mmol),
ethanol (5 mL) and Fe3O4–BF3 (5 mg), ultrasonic irradiation (40 kHz, 200 W) at room temperature
a
Yields refer to isolated pure products
and 4aw). As it is clear from the obtained results, the presented methodology can be
used in order of oxygen-, sulfur- and nitrogen-containing heteroaromatic aldehydes.
Interestingly, cyclic ketones such as cyclopentanone, cyclohexanone and cyclohep-
tanone, as well as aryl–alkyl ketones, diaryl ketones and tetralones, were successfully
reacted with amines and trimethylsilyl cyanide to afford corresponding a-aminon-
itriles in reasonable yields and in short reaction times (Table 2, entries 4bc-bm and
4 bp). In the case of aliphatic amines, relatively slow reaction rates occurred due to the
123

M. Shekouhy et al.
unstable nature of formed aliphatic imines in the presence of water (Table 2, entries
4ae, 4af, 4aq, 4ah, 4ai, 4ar, 4au, 4av and 4aw).
Oxindole derivatives exhibit an extensive range of biological effects. For
example, indolin-2-one (Sunitinib) has been widely used in the treatment of
gastrointestinal stromal tumors, and metastatic renal cell cancer. Oxindole-Schiff
base copper (II) complexes have shown potential antitumor activity towards
different cells. Moreover, indolidan and adibendan are used for the treatment of
congestive heart failure as these have strong vasodilatory, positive inotropic and
inodilatory actions. Amino methylene oxindole derivatives are useful as antihyper-
tensive agents and oxindole-oxazolidinone derivatives are the most important class
of antimicrobial compounds. Artificial oxindole-containing compounds also exhibit
useful pharmaceutical properties, including growth hormone secretagogues, anal-
gesic, anti-inflammatory, and serotonergic. Most of these compounds contain a
variety of substituent at the C-3 position of oxindole [66–78]. Considering these
facts, new a-aminonitriles bearing an indoline moiety were synthesized via a one-
pot three-component condensation reaction between isatin derivatives (5), amines
and trimethylsilyl cyanide in the presence of Fe3O4–BF3 magnetic nanoparticles
under ultrasonic irradiation at room temperature. Moreover, acenaphthenequinone
(6) was applied successfully for the first time and desired a-aminonitriles were
obtained in excellent yields and relatively short reaction times; obtained results are
summarized in Table 3 (Scheme 2).
Adenine is a nucleobase with a variety of roles in biochemistry, including cellular
respiration and protein synthesis as a chemical component of DNA and RNA.
Moreover, it is the certain backbone of various commercial antivirus drugs such as
Adefovir, Tenofovir and Adefovir dipivoxil. In addition, various a-aminonitrile
compounds have been reported for their biological as well as pharmaceutical
properties such as reversible inhibition of dipeptidyl peptidase-4 (DPP-4) for the
treatment of diabetes. As a stimulant drug, amphetaminil has been used for the
treatment of obesity and narcolepsy. Saxagliptin is a new anti-diabetic drug that is
classified as a potent dipeptidyl peptidase-4 (DPP-4) inhibitor agent. Another most
important dipeptidyl peptidase-4 (DPP-4 inhibitor) is vildagliptin, which has been
used as an efficient anti-diabetic drug in recent years. Based on these facts,
combination of amionitrile moiety with an adenine backbone may be lead to the
construction of new biological active compounds with unique and special
properties. With this point of view, we examined our method for the synthesis of
a new adenine-containing a-aminonitrile. For this, compound (1b) was synthesized
in two steps. At first, 4-hydroxybenzaldehyde (1c) was reacted with 1,3-dibromo-
propane (8) to produce 4-(3-bromopropoxy)benzaldehyde (9). Finally, presilylated
adenine (10) was added to compound (9) and aldehyde (1b) was obtained in good
yield (Scheme 3).
To assess the capability and efficiency of our methodology with respect to the
reported procedures for the synthesis of a-aminonitriles, results of the application of
these methods are tabulated in Table 4. As it is clear from Table 4, our presented
methodology was more efficient.
The possibility of recycling the catalyst was examined using the one-pot three-
component reaction between benzaldehyde (1 mmol), aniline (1.2 mmol) and
123

Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
Table 3 The condensation reaction of isatins (5) as well as acenaphthenequinone (6) with amines and
TMSCN in the presence of magnetic Fe3O4–BF3 under ultrasonic irradiation at room temperature
Entry
7aa
Carbonyl
compound
Amine
Product
Time
(min)
Yield
(%)a
M.P. (°C)
O
O
8
89
93–94
NH2
NH
O
O
NC
NH
(91–92 [65])
NH
O
NH2
CH3
7ab
7ac
6
92
101–103
NH
O
NC
NH
(99–101 [65])
H3
C
NH
O
O
8
8
90
94
109–111
NH2
NH
NC
NH
O
NH
(110–112 [65])
CH3
H3
O
C
C
O
O
NH2
Br
7ad
118–120
NH
NC
NH
NH
(119–121 [65])
Br
CH3
H3
O
O
O
O
7ae
7af
10
8
94
91
133–135
H
NH2
N
(135–137 [65])
CN
O
O
O
NH2
134–136
H
N
(138–140 [65])
CN
CH3
CH3
NH2
O
O
7ag
10
93
167–169
H
N
(168–170 [65)
CN
Br
Br
a
Isolated yields
trimethylsilyl cyanide (1.2 mmol) under the optimized conditions. After completion
of the reaction, catalyst was removed with a magnet washed with ethanol, dried and
reused. After the isolation of catalyst, water (20 mL) was added and insoluble crude
products were filtered and recrystallized from ethanol/water (4:1). In the case of oil
products, appropriate amounts of ethyl acetate (5 mL, two times) were added, the
organic layer was washed with brine (5 mL), dried (MgSO4), and concentrated. The
residue was chromatographed over silica gel (15-% ethyl acetate in n-hexane) to
give a pure product. Recovered Fe3O4–BF3 magnetic nanoparticles were reused 15
times in the condensation of benzaldehyde (1 mmol), aniline (1.2 mmol) and
trimethylsilyl cyanide (1.2 mmol) and any loss of efficiency was not observed
(Fig. 6). In order to study the stability of the catalyst structure, the boron content of
the catalyst was determined to be at about 0.5 mmol g-1 after the 15th reuse. So, it
has been concluded that the catalyst structure is stable under the reaction condition
and boron is strongly bonded to the surface of Fe3O4 magnetic nanoparticles and
was not leached during the reaction.
123

M. Shekouhy et al.
R3
NH
O
NC
X
X
O
O
N
N
H
H
(5)
R3 NH2
+
TMSCN
X= H, CH3
Fe3O4-BF3 MNPs
Sonication )))))))
r.t.
R3
NH
NC
O
O
O
(6)
(7aa-g)
Scheme 2 Ultrasound-assisted one-pot three-component condensation of isatin derivatives (5) and
acenaphthenequinone (6) with amines and trimethylsilyl cyanide in the presence of Fe3O4–BF3 at room
temperature
CHO
Br
CHO
K2CO3, TBAB
CH3CN, Reflux
+
Br
O
Br
HO
(1c)
(8)
(9)
Me3Si
NH
N
N
N
NH2
CHO
N
N
N
(10)
N
SiMe3
N
THF / TBAF / Reflux
O
(1b)
NH2
HN
NH2
N
+
TMSCN
CN
N
N
(2a)
(3)
N
(11)
Fe3O4-BF3 MNPs
Sonication
O
50 min / 79%
Scheme 3 Synthesis of an adenine-containing starting material for the synthesis of an adenine-
containing a-aminonitrile (11)
123

Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
Table 4 Comparison of the condensation of benzaldehyde and aniline with trimethylsilyl cyanide using
the reported methods versus the present method
Entry Conditions
Time
(min)
Yield
(%)
Refs.
1
2
3
InCl3 (20 mol%), Dry tetrahydrofurane, room temperature
360
600
210
75
84
90
[19]
[20]
[21]
BiCl3 (10 mol%), acetonitrile, room temperature
Montmorillonite KSF clay, 1.0 g, dichloromethane, room
temperature
4
5
Silica-based scandium(III) (3 mol%), dichloromethane, room
temperature
SO42-/ZrO2 (10 mol%), Dry tetrahydrofurane, N2 atmosphere,
room temperature
840
90
94
93
[22]
[23]
6
7
Guanidine hydrochloride (3 mol%), ethanol, 40 °C
Xanthane sulfuric acid (6 mol%), Dry acetonitrile, room
temperature
60
65
94
97
[31]
[32]
8
Silica sulfuric acid (25 mol%), dichloromethane, room
temperature
360
88
[34]
9
SBA-15 supported sulfonic acid (5 mol%), solvent-free 50 °C
Fe3O4–BF3 magnetic nanoparticles (50 mg), ethanol, ultrasonic
irradiation, room temperature
5
5
100
94
[35]
This
10
work
A plausible mechanism for the preparation of titled compounds in the presence of
Fe3O4–BF3 as a magnetically separable Lewis acid catalyst is described in
Scheme 4. As it is shown in Scheme 4, at first, desired imines (12) will be produced
with the condensation of carbonyl compounds (1) and amines (2). In the next step,
prepared imines will be attacked with the cyanide ion that is released from the
trimethylsilyl cyanide (3) in the presence of water to produce the desired a-
aminonitriles. The crucial role of Fe3O4–BF3 as a magnetically separable Lewis acid
catalyst is to increase the electrophilicity of carbonyl compounds toward the
nucleophilic attack of amines with the interaction of borane and oxygen of carbonyl
compounds. Moreover, readily formed imines will be activated toward the
nucleophilic attack of cyanide ions with the interaction of borane and the nitrogen
of imines.
Moreover the energy-based efficiency (ge) of the reaction was calculated for the
model reaction. Based on the assumption that the mechanical energy generated by
the ultrasonic waves is reduced to heat, the dissipated ultrasonic power Up was
calculated from the rate of temperature increase as:
dT
Up ¼ CpM Á
dt
where Cp is the heat capacity of the solvent at constant pressure (J g-1 K-1), M is
the mass of solvent (g) and dT/dt is temperature rise per second [79]. The dT/dt was
determined to be at about 1 K s-1 under the applied conditions. So, based on this
equation and for ethanol as solvent (Cp = 2.44 J g-1 K-1, 3.945 g) and 5 min
123

M. Shekouhy et al.
Fig. 6 The reusability and recyclability of magnetic Fe3O4–BF3 catalyst
Fe3O4
R2
R1
F
F
H2N R3
B
(1)
O
(2)
O
R1
R2
R3
HN
R2
H
O
Fe3O4
F
Fe3O4
B
B
F
F
R1
F
R3
R2
R1
H2O
R2 CN
N
R3
F
R1
N
Fe3O4
B
F
H
(12)
CN
Si
(4aa-bp)
H3C
CH3
H2O + TMSCN
O H
H
H3C
(3)
Scheme 4 The plausible mechanism for the synthesis of a-aminonitriles in the presence of Fe3O4–BF3
123

Magnetic Fe3O4–BF3: highly efficient Lewis acid catalyst…
irradiation (300 s), the Up was calculated to be at around 2887.74 Jules. The
electrical power supply of the ultrasound generator worked with 280-W power and
the power of produced ultrasonic irradiation was calculated to be 200 W. The
energy-based efficiency was calculated as follows, where Pu is the ultrasonic power
and Pe is the electrical power:
Pu À Up
ge ¼
Pe
Using this equation and for applied conditions (5 min ultrasonic irradiation, 5-mL
ethanol as solvent), the energy-based efficiency of the applied method for the model
reaction was calculated to be 0.67.
Conclusions
In summary, we have reported a new, highly efficient and sustainable catalytic
system for the synthesis of a-aminonitriles. In this context, covalence bonding of
BF3 as a strong Lewis acid on the surface of Fe3O4 magnetic nanoparticles changes
this material from a very hazardous and non-recyclable chemical to a heterogeneous
magnetically separable solid Lewis acid. Application of this catalyst not only offers
substantial improvements in the reaction rates and yields, but also avoids the use of
hazardous catalysts or solvents. The promising points for the presented method-
ology are efficiency, generality, high yields, short reaction times, cleaner reaction
profiles, ease of product isolation, simplicity and, finally, agreement with the green
chemistry protocols which all make it a useful and attractive process for the
synthesis of a-aminonitriles.
Acknowledgments We gratefully appreciate the Shiraz University Research Council for their financial
support of this work.
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