Synthesis of N-methyl imines in the presence of poly(N-vinylpyridine) as a reusable solid base catalyst by a mechanochemical process

Article abstract of DOI:10.1007/s11164-016-2672-y

The synthesis of N-methyl imines was performed in the presence of catalytic amounts of poly(4-vinylpyridine) in high yields and rapidly at room temperature by a ball milling process. This new method has some advantages including good yields for relatively unreactive carbonyl compounds and short reaction times as well as being green in terms of avoiding the use of toxic reagents and solvents. The major advantage of this process is that the catalyst can be easily regenerated and reused several times without any significant loss of activity.

Full text of DOI:10.1007/s11164-016-2672-y

Res Chem Intermed
DOI 10.1007/s11164-016-2672-y
Synthesis of N-methyl imines in the presence of
poly(N-vinylpyridine) as a reusable solid base
catalyst by a mechanochemical process
Nader Ghaffari Khaligh1,2 Hanna S. Abbo3
•
•
Salam J. J. Titinchi3
Received: 1 April 2016 / Accepted: 22 July 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract The synthesis of N-methyl imines was performed in the presence of
catalytic amounts of poly(4-vinylpyridine) in high yields and rapidly at room
temperature by a ball milling process. This new method has some advantages
including good yields for relatively unreactive carbonyl compounds and short
reaction times as well as being green in terms of avoiding the use of toxic reagents
and solvents. The major advantage of this process is that the catalyst can be easily
regenerated and reused several times without any significant loss of activity.
Keywords Recyclable solid base Á Mechanochemical process Á N-methyl imine Á
Poly(4-vinylpyridine)
Introduction
Compounds containing an azomethine group (–CH=N–), known as Schiff bases are
produced by the condensation of a primary amine with an aldehyde or ketone. Schiff
bases of aromatic aldehydes, having an effective conjugation system, are
substantially more stable and more readily synthesized, while those which contain
alkyl substituents are relatively unstable and are readily polymerized. Schiff bases
and their derivatives possess interesting biological properties viz., anti-inflamma-
tory, analgesic, anticonvulsant, antituberculous, antitumor, anti-HIV and antimi-
crobial activity [1–3]. In addition, they also play an important role in the treatment
&
Nader Ghaffari Khaligh
ngkhaligh@gmail.com
1
2
Research House of Professor Reza, Education Guilan, Rasht, District 1 41569-17139, Iran
Nanotechnology and Catalysis Research Center, 3rd Floor, Block A, Institute of Postgraduate
Studies, University of Malaya, 50603 Kuala Lumpur, Malaysia
3
Department of Chemistry, University of the Western Cape,
P/B X17, Bellville, Cape Town 7535, South Africa
123

N. G. Khaligh et al.
of leishmaniasis, trypanosomiasis, and malaria [4–6]. Furthermore, they have found
widespread use in asymmetric synthesis of a-aminonitriles, preparation of
secondary amines by hydrogenation, and cycloaddition reactions [7–9]. These
compounds have been employed as organocatalysts, ligands for metal complexes,
drug design, and the syntheses of heterocyclic compounds [10, 11].
Various methods for the synthesis of imines include (a) the use of polymer-
supports [12], (b) Lewis acids [13–16], (c) P4O10/SiO2 [17], (d) molecular sieves
[18], (e) Mg(ClO4)2 [19], and (f) infrared [20], microwave [21, 22] or ultrasound
irradiations [23]. The synthesis of N-methyl imines involves the use of an aqueous
solution of methylamine or its salt, i.e., methylamine hydrochloride as the
methylamine scaffold source and then using classical routes [24–26].
Alternative protocols include the use of N,N-bis(trimethylsilyl) methylamine in
the presence of trimethylsilyl trifluoromethanesulfonate in chlorinated solvents such
as dichloromethane (DCM) or dichloroethane (DCE) [27] and methylamine gas [28]
or 1,3-dimethylurea dispersed on montmorillonite K10 under microwave irradiation
as the methylamine precursors [29]. In spite of this, even the most convenient
methods for the synthesis of N-methyl imines have several inherent disadvantages,
such as gas handling, the use of toxic and volatile organic solvents, and long
reaction times.
Coherent efforts have over the years been made to develop chemical technologies
able to reduce or eliminate the use of toxic organic solvents in protocols aimed at
securing pure N-methyl imines. The ball milling process was introduced to manage
the global problems of pollution [30, 31] and incorporated as a major component in
various reactions [32–39]. The applications of solid bases are not only of interest
from an environmental point of view, but in many cases, also offer considerable
synthetic advantages such as their reusability and milder conditions. Application of
P(4-VP) for the alkylation of isobutene to produce alkylates of high octane numbers
[40], the selective methanolysis of methyl and methylene bromides [41], the
chemoselective silylation of alcohols, phenols, and N-tert-butoxycarbonyl (N-Boc)
protection of amines [42] has been demonstrated. The influence of the nature of a
base on the synthesis of N-methyl imines has been reported [43].
Herein, a simple, efficient and environmentally benign method of mild reaction
conditions is presented for the synthesis of various N-methyl aryl imines in the
presence of the inexpensive solid base catalyst Poly(4-vinylpyridine) [P(4-VP)].
Experimental
General
All chemicals were purchased from either Merck or Fluka Chemical Companies. All
yields refer to the isolated products. Known products were characterized by their
melting point and FTIR, NMR spectral data, and comparison with the literature.
Two new products were characterized by their melting point and FTIR, with NMR
spectral and elemental analysis. The purity determination of the substrates and
123

Synthesis of N-methyl imines in the presence of…
reaction monitoring was accompanied by TLC using silica gel SIL G/UV 254
plates.
The infrared (IR) spectra were run on a Perkin–Elmer 781 spectrophotometer
using KBr pellets for solid and neat for liquid samples in the range of
4000–400 cm-1. The reaction conversions were measured by GC–MS on an
Agilent GC-Mass-6890 instrument under 70 eV conditions. The 1H NMR spectra
were recorded on a Bruker Avance 300 or 400 MHz and the 13C NMR were run on
a Bruker Avance 75 or 100 MHz instrument (d in ppm). Melting points were
recorded on a Bu¨chi B-545 apparatus. Grinding was performed in a Retsch PM 100
planetary ball mill using a 50 mL reaction chamber and 7 mm stainless steel balls
with sun wheel speed of 400 min-1
.
General procedure for N-methyl imines formation
Poly(4-vinylpyridine) (1.0 g) was ground with a mixture of methylamine
hydrochloride (10 mmol) and appropriate carbonyl compound (5 mmol) (molar
ratio CH3NH2ÁHCl/ArCHO = 2:1) in a planetary ball mill along with two stainless
steel balls of 7 mm diameter at room temperature. After completion of the reaction
(monitored by TLC), hot absolute ethanol (5 mL) was added to the reaction mixture,
which was then filtered. The precipitated P(4-VP)ÁHCl was isolated while the
filtrate/supernatant was examined by GC. No signal of the catalyst P(4-VP) was
detected, confirming that the catalyst was converted to its hydrogen chloride salt
form. The base catalyst was recovered by neutralization using NaHCO3. The filtrate
was evaporated under reduced pressure, and the pure product was obtained upon
recrystallization from absolute ethanol. IR and 1H NMR spectra of known
compounds were in agreement with those reported in the literature [43–45].
Recycling of P(4-VP)
After each run, P(4-VP)ÁHCl was neutralized via the incremental addition of sodium
bicarbonate until pH [6 and then extracted with EtOAc (3 9 5 mL), dried, and
evaporated to a residue, which was dried overnight at 50 8C under vacuum. The FT-
IR spectra of fresh and recycled P(4-VP) were identical in all aspects.
The spectral data of new and some representative products
N-(4-nitrobenzylidene)methanamine (Table 2, entry 4) yellow solid, m.p.
1
104–106 °C; IR (KBr): mmax 2975, 2910, 1649, 1598, 1510, 1444, 1347 cm-1; H
NMR (CDCl3, 300 MHz, d ppm): d 3.56 (d, J = 1.6 Hz, 3H, CH3), 7.86 (d,
J = 8.4 Hz, 2H, CH2), 8.20 (d, J = 8.4 Hz, 2H, CH2), 8.38 (q, J = 1.6 Hz, 1H,
N=CH).
N,N-dimethyl-4-((methylimino)-methyl)aniline (Table 2, entry 7) yellow solid,
m.p. 54–56 °C; IR (KBr): mmax 3042, 1640, 1560, 1491, 1412, 1269, 1189,
1152 cm-1; 1H NMR (CDCl3, 300 MHz, d ppm): d 3.02 (s, 6H, N(CH3)2), 3.38 (s,
123

N. G. Khaligh et al.
3H, N-CH3), 6.83 (d, J = 8.2 Hz, 2H, Ar-H), 7.43 (d, J = 8.2 Hz, 2H, Ar-H), 8.16
(s, 1H, N=CH).
N-(pyridin-4-ylmethylene)methanamine (Table 2, entry 15) colorless oil; IR
(neat): mmax 3045, 1648, 1581, 1566, 1506, 1463, 1393, 1250, 1211, 1140,
1042 cm-1; 1H NMR (CDCl3, 300 MHz, d ppm): d 3.62 (d, J = 1.8 Hz, 3H, CH3),
7.56 (d, J = 8.4 Hz, 2H, Ar-H), 8.62 (d, J = 8.4 Hz, 2H, Ar-H), 8.85 (q,
J = 1.6 Hz, 1H, N=CH) ppm; 13C NMR (CDCl3, 75 MHz, d ppm): d 48.9, 120.4,
127.3, 129.9, 148.7, 159.7; Calcd for C7H8N2: C 69.97, H 6.71, N 23.31 %; found:
C 69.84, H 6.63, N 22.97 %.
N-(Furan-2-ylmethylene)methanamine (Table 2, entry 16) colorless oil; IR (neat):
mmax 3052, 1652, 1588, 1561, 1501, 1461, 1389, 1254, 1208, 1146, 1038 cm-1; 1H
NMR (CDCl3, 300 MHz, d ppm): d 3.58 (d, J = 1.8 Hz, 3H, CH3), 6.01 (d,
J = 2.8 Hz, 1H, CH), 6.23 (dd, J = 0.8 and 2.8 Hz, 1H, CH), 7.22 (d, J = 0.8 Hz,
1H, CH), 8.94 (q, J = 1.8 Hz, 1H, N=CH); 13C NMR (CDCl3, 75 MHz, d ppm): d
49.3, 111.9, 112.0, 132.3, 146.5, 156.4; Calcd for C6H7NO: C 66.04, H 6.47, N
12.84 %; found: C 65.92, H 6.36, N 12.97 %.
Results and discussion
In order to determine the optimal reaction conditions for the ball milling protocol,
4-nitrobenzaldehyde and methylamine hydrochloride were selected as reagents in a
model reaction (Scheme 1). Initially, equimolar amounts of 4-nitrobenzaldehyde
and CH3NH2ÁHCl were milled together in the absence of the catalyst P(4-VP) for
1 h. (Table 1, entry 1). The yield was poor and starting aldehyde was recovered. In
the presence of 0.5 g P(4-VP) as base catalyst and with milling for 30 min, there
was afforded a crude product as a mixture of 4-nitrobenzaldehyde and N-(4-
nitrobenzylidene) methanamine in the ratio 24:76 (GC–MS analysis) (Table 1, entry
2). In order to improve the yield, the reaction was carried out with a two fold excess
of CH3NH2ÁHCl and variation of the amount of P(4-VP) (0.5–1.0 g) and milling
time (30–60 min) was then investigated. Increasing the amount of solid base to 0.8
and 1.0 g resulted in yield increases from 88 to 94 %, respectively (Table 1, entries
3 and 4). However, further increases of the amount of catalyst, i.e., 1.2 g of P(4-VP)
did not enhance the yield (Table 1, entry 6). Similarly prolonging the milling time
to 60 min did little to improve the yield (Table 1, entry 5). Thus, best yields were
obtained when the reaction was performed by ball milling 5 mmol of aldehyde,
10 mmol of CH3NH2ÁHCl, and 1.0 g of P(4-VP) for 30 min.
Scheme 1 Synthesis of N-methyl imines in the presence of P(4-VP)
123

Synthesis of N-methyl imines in the presence of…
Table 1 The effect of P(4-VP) and milling time for a mixture of 4-nitrobenzaldehyde and methylamine
hydrochloride
Entry
Amount of catalyst (g)
Time (h)
Yield (%)a
1
2
3
4
5
6
–
1
8b
76
88
94
96
96
0.5
0.8
1.0
1.0
1.2
0.5
0.5
0.5
1
1
Reaction conditions: 4-Nitrobenzaldehyde 5.0 mmol, N-methylamine hydrochloride 10.0 mmol, room
temperature, and solvent-free
a
Determined by GC–MS
b
Equimolar amounts of reactants were milled
It may be concluded that the solid base catalyst plays a crucial role, apparently
through slowly scavenging liberated HCl.
To investigate the scope of this reaction, different aryl aldehydes were subjected
to the optimized reaction conditions. Table 2 illustrates that the present method is
most effective for formation of the N-methyl imines. The aldehydes bearing
electron-withdrawing groups gave higher yields in shorter reaction times than those
with electron-donating substituents. Aldehydes with electron-withdrawing sub-
stituents in the ortho-position such as 2-nitrobenzaldehyde gave the highest yield
(Table 2, entry 11), whereas the yield of 2-methoxy benzaldehyde having an
electron-releasing substituent was lower (Table 2, entry 12). Imines formed from
aldehydes with electron-releasing substituents in the ortho position were obtained
with higher yield compared to those of the corresponding para-position (Table 2,
entries 5 and 12). It seems that the steric interaction between the ortho-substituent
and carbonyl group of aldehyde causes the displacement of the carbonyl group out-
of-plane of the aromatic ring; therefore, ortho-isomers have higher electrophilicity
than meta- and para-isomers [43].
As expected, electron-releasing groups viz., –OCH3 decrease the electrophilicity
´
of the carbonyl carbon. In this regard Radulovic et al. [43] reported that use of
4-methoxybenzaldehyde/CH3NH2ÁHCl/NaHCO3 in the ratio of 1:5:5 afforded 65 %
yield after 3 h by grinding. In the current method, a 78 % yield of the corresponding
N-methyl imine was obtained in 1 h in the presence of P(4-VP) under optimized
conditions (Table 2, entry 5). Salicylaldehyde gave much lower yields of the
respective N-methyl imine in strong basic conditions [43], but using the current
conditions, the expected imine was obtained in 82 % yield (Table 2, entry 8).
The presence of the 4-dimethylamino group in 4-dimethylaminobenzaldehyde
reduces the electrophilicity of the carbonyl carbon through resonance. Thus,
synthesis of N,N-dimethyl-4-[(methylimino)-methyl]aniline from the condensation
between 4-dimethylaminobenzaldehyd with methylamine failed in the presence of
NaHCO3 as the base at room temperature [43]. Also, due to deprotonation of the
123

N. G. Khaligh et al.
Yield (%)a
Table 2 The reaction of aryl
aldehydes with methylamine
hydrochloride in the presence of
P(4-VP)
Entry Aldehyde
Time (h)
1
2
3
4
C6H5–CHO
1
91
94
92
94
4-Cl–C6H4–CHO
4-CH3–C6H4–CHO
4-O2N–C6H4–CHO
1
1
0.5
(0.5,0.5,0.5)b
(94,93,92)b
5
4-CH3O–C6H4–CHO
4-HO–C6H4–CHO
4-(CH3)2N–C6H4–CHO
Salicylaldehyde
1
1
2
1
1
1
78
6
89
86
82
78
81
98
83
85
IR and 1H NMR spectra of
known compounds were in
agreement with those reported in
the literature [43, 44]
7
8
9
2-Cl–C6H4–CHO
Reaction conditions: aryl
aldehyde 5.0 mmol,
10
11
12
13
2-CH3–C6H4–CHO
2-O2N–C6H4–CHO
2-CH3O–C6H4–CHO
0.5
1
CH3NH2ÁHCl 10.0 mmol,
P(4-VP) 1.0 g, room
temperature, and solvent-free
3,4-(CH3O)2–C6H3–
CHO
1
a
Isolated yields
b
14
15
16
Vanilline
1
89
90
78
The reaction time and product
yield after three consecutive
recycles in presence of
recovered solid acid
Pyridine-4-carbaldehyde
Furfural
1
1.16
phenolic group and forming the sodium salt of salicylaldehyde, the poorest yield
was reported for the grinding of salicylaldehyde with CH3NH2ÁHCl in presence of
NaHCO3 in a molar ratio ArCHO/CH3NH2ÁHCl/NaHCO3 = 1:5:5 [43]. However,
using the current method, 4-dimethylaminobenzaldehyd and salicylaldehyde react
with solid amine CH3NH2ÁHCl in a ball-mill at room temperature within 2 and 1 h
to give 86 and 82 % yield of product, respectively (Table 2, entries 7 and 8). It was
interesting to note that heteroaromatic aldehydes (Table 2, entry 15 and 16) were
smoothly converted to their corresponding N-methyl imines without any by-
products [46].
The reusability of recovered P(4-VP) was exemplified by a model reaction which
afforded the N-methyl imine product in 94–92 % yield after four consecutive runs.
The average time for four consecutive runs was 30 min and a 100 % conversion in
all cases (monitored by GC–MS), which clearly demonstrates the practical
recyclability of this reagent (Table 2, entry 4). The P(4-VP) catalyst remains active
even after the fourth cycle, confirming the stability of the polymer under the
reaction conditions. Also in the present method, the catalyst does not contain any
metal ion [43].
Although a detailed mechanism for the current transformation has not yet been
established, a plausible catalytic cycle for the regeneration of P(4-VP) has been
proposed, as shown in Scheme 2. Thus, P(4-VP) acts as a proton scavenger to
facilitate the liberation of methyl amine in the first step. The nucleophilic attack on
the carbonyl group by methyl amine is catalysed by a base catalyst in the second
step. Dehydration of the intermediate hydroxyl amine then affords the product.
Recovery of the base catalyst is performed by neutralization of the used catalyst by
123

Synthesis of N-methyl imines in the presence of…
Scheme 2 Proposed mechanism for the preparation of N-methyl imines in the presence of P(4-VP)
the incremental addition of NaHCO3 as the cheapest chemical available for
neutralization. Neutralized waste is primarily water and dissolved sodium chloride,
which is non-hazardous. Further investigations aimed at fully elucidating the precise
mechanism of this reaction are currently underway in our laboratory.
Conclusion
A simple and efficient method for the preparation of various N-methyl imines by
using P(4-VP) as a solid base catalyst has been developed. Methylamine
hydrochloride and P(4-VP) are commercially available and safe to handle. The
ethanolic mixture of P(4-VP)ÁHCl is readily separated from the reaction mixture by
filtration and recovered without any significant loss in activity. The methodology
has several other advantages viz., the use of ethanol for extracting and
recrystallization, the elimination of hazardous solvents during the reaction, the
obviation of handling an anhydrous gas in an evacuated container, mild reaction
conditions delivering good to excellent yields, and simple experimental procedures.
The major advantage of this process is the use of an environmentally benign catalyst
123

N. G. Khaligh et al.
that can be easily regenerated and reused several times without any significant loss
of its activity.
Acknowledgments The authors are grateful to staff members in the Analytical and Testing Center of the
Research House of Professor Reza and the University of the Western Cape and the University of Malaya
for partial support.
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