N-Formylation of amines using arylhydrazones of malononitrile and a Cu(II) complex under eco-friendly conditions at room temperature

Article abstract of DOI:10.1016/j.ica.2020.119938

In this work, we report the synthesis of formamides via solvent free N-formylation of amines using known arylhydrazones of malononitrile including sodium 2-(2-(dicyanomethylene)hydrazinyl)benzenesulfonate (I), 2-(2-(dicyanomethylene)hydrazinyl) benzoic acid (II) and its Cu(II) complex (III) as catalysts at room temperature. These catalysts are highly active and the scope of the method was investigated using several heterocyclic, aromatic and aliphatic amines as substrates, which produced the corresponding formamides in high yields. The remarkable advantages of this method are the elimination of toxic solvents, operational simplicity, easy workup procedure, excellent yields and avoidance of column chromatography.

Full text of DOI:10.1016/j.ica.2020.119938

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Research paper
N-Formylation of amines using arylhydrazones of malononitrile and a Cu(II)
complex under eco-friendly conditions at room temperature
Mahmoud Nasrollahzadeh, Nayyereh Sadat Soheili Bidgoli, Bruno G.M.
Rocha, Armando J.L. Pombeiro, Kamran Mahmudov
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https://doi.org/10.1016/j.ica.2020.119938
ICA 119938
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Inorganica Chimica Acta
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Please cite this article as: M. Nasrollahzadeh, N.S.S. Bidgoli, B.G.M. Rocha, A.J.L. Pombeiro, K. Mahmudov, N-
Formylation of amines using arylhydrazones of malononitrile and a Cu(II) complex under eco-friendly conditions
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N-Formylation of amines using arylhydrazones of malononitrile and a
Cu(II) complex under eco-friendly conditions at room temperature
Mahmoud Nasrollahzadeh,a,* Nayyereh Sadat Soheili Bidgoli,a Bruno G. M. Rocha,b,*
Armando J. L. Pombeiro,b and Kamran Mahmudov b
aDepartment of Chemistry, Faculty of science, University of Qom, P. O. Box 37185-359, Qom, Iran
bCentro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001
Lisbon, Portugal
ABSTRACT
In this work, we report the synthesis of formamides via solvent free N-formylation of amines
using
known
arylhydrazones
of
malononitrile
including
sodium
2-(2-
(dicyanomethylene)hydrazinyl)benzenesulfonate (I), 2-(2-(dicyanomethylene)hydrazinyl)
benzoic acid (II) and its Cu(II) complex (III) as catalysts at room temperature. These
catalysts are highly active and the scope of the method was investigated using several
heterocyclic, aromatic and aliphatic amines as substrates, which produced the corresponding
formamides in high yields. The remarkable advantages of this method are the elimination of
toxic solvents, operational simplicity, easy workup procedure, excellent yields and avoidance
of column chromatography.
Keywords: N-Formylation; Amines; Formamides; Solvent-Free; Copper; Arylhydrazones of
malononitrile
*E-mail: mahmoudnasr81@gmail.com (M. Nasrollahzadeh).
*E-mail: bruno.g.m.rocha@tecnico.ulisboa.pt (B. G. M. Rocha)
1

1. Introduction
Formamides as a very important class of amine derivatives have attracted the attention of
many chemists and pharmacists due to their extensive range of applications in diverse areas
of sciences and industries from synthetic organic chemistry to large-scale production [1].
They have been widely used as intermediates in the preparation of various pharmaceutical
compounds, especially cancer chemotherapeutic agents [1]. Moreover, formamides are
employed for the protection of the nitrogen of amines and in the production of isocyanides
and formamidines [2,3]. Formamides can also act as Lewis base catalysts in the
hydrosilylation of carbonyl compounds, preparation of acid chlorides and allylation [4,5].
Owing to the wide applications of formamides, the development of novel methods for
their preparation using formylation reagents has attracted considerable interest [6-10]. Many
processes have been studied for the formamide preparation by different reagents such as
chloral [11], acetic formic anhydride [12], activated formic acid by N,N′-
dicyclohexylcarbodiimide (DCC) [13], 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI) [14] activated formic esters [15,16], NH4HCO2 [17], polyethylene glycol 400 (PEG-
400) [18] and 2,2,2-trifluoroethyl formate [19].
The different methods reported for the synthesis of formamides suffer from certain
drawbacks, such as harsh reaction conditions, low yields, use of toxic and expensive
formylating reagents and expensive homogeneous and heterogeneous catalysts, and formation
of by-products. Thus, there is still a high demand to improve the common synthetic methods,
namely by reducing or avoiding the use of hazardous and expensive compounds.
Among the important formylating agents, HCOOH has been widely investigated and it
mostly displayed efficient ability in the N-formylation of amines because of its low-cost, and
accessibility from biomass-derived renewable materials [6].
2

In recent years, the common approaches for the preparation of formamides have been
based on the N-formylation of amines using HCOOH as a common formylating agent and a
variety of catalysts such as transition metal/metal oxide catalysts (NiO, ZnO, etc.), inorganic
solid oxides (zeolite, silica gel, alumina, etc.) and acidic catalysts (AlCl3, ZnCl2, NiCl2, etc.)
[6]. However, the use of most of these catalysts has several disadvantages, such as high cost,
harsh synthetic procedures, tedious work-up, low yields, and the utilization of moisture
sensitive and toxic/expensive reagents. Thus, it is desirable to develop more convenient
methods for the production of formamides, namely by using organocatalysts or their metal
complexes under simple conditions and in the absence of toxic and expensive solvents or
reagents.
We have reported [20,21] the synthesis in good yields of arylhydrazones of malononitrile,
such as (I) and (II), and of a copper complex (III) bearing II (in basic form) as ligand
(Scheme 1).
Na
N
O
O
N
N
CN
NC
O
C
C
H
N
S
N
N
Cu
Cu
O
C
N
O
N
O
O
N
H
OMe
MeO
MeO
N
H
I
NH
Cu
H
O
NC
N
O
O
O
N
N
C
C
H
C
O
H
N
O
Cu
N
MeO
N
C
N
N
N
NC
II
III
Scheme 1. Schematic representations of I – III [20,21].
In the present work and in continuation of our studies on the preparation of various
aroylhydrazone catalysts and their application in organic synthesis [22-26], we have focused
3

on the synthesis of formamides in high yields via N-formylation of various amines with
HCOOH (formic acid) under mild conditions using the organo compounds (I) and (II), or the
Cu(II) complex (III) as catalysts (Scheme 2).
O
R
R
I II III
( or
)
N
C
NH + HCOOH
solvent-free, r.t.
H
R'
R'
Scheme 2. Preparation of formamides using catalysts I, II or III.
2. Experimental
2.1. Tools and reagents
All chemicals used in this study were obtained from Merck/Sigma Aldrich Chemical Co. and
directly used as received without further purification. FTIR spectra were recorded using a
Perkin Elmer 781 spectrophotometer by mixing the samples with KBr, pressing into pellets,
and scanning from 4000 to 400 cm-1. The NMR spectra were recorded using a Bruker Avance
DRX-300 MHz instrument. An electrothermal 9100 apparatus was applied for measuring the
melting points.
2.2. Preparation of arylhydrazones of malononitrile (I and II)
The synthesis and characterization of compounds (I) and (II) were carried out according to
our previous work [20,21].
2.3. Preparation of copper(II) complex (III)
Green crystals of complex (III) were prepared according to our reported work by reacting
compound (II) with Cu(CH3COO)2∙H2O in methanol under reflux conditions for 0.5 h [21].
2.4. General experimental procedure for the preparation of formamides
A mixture of amine (0.5 mmol), HCOOH (99%, 1 mmol) and catalyst (typically 0.030 g, i.e.,
0.12, 0.14 or 0.024 mmol of catalyst I – III, respectively) was stirred at room temperature for
4

appropriate time. Upon completion of the reaction (followed by TLC), the reaction mixture
was washed with water and then treated with EtOAc to separate the pure product. The FTIR
and NMR spectral data were found to be identical with those reported in our previous works
[7-10].
N-(2-Hydroxyphenyl) formamide
M.p. 130-131 °C (lit. 129-131°C [27])
FT-IR (KBr, cm-1) 3376, 3104, 1656, 1591, 1535, 1453, 1378, 1280, 1251, 1206, 1098, 751,
664.
1H NMR (400 MHz, CDCl3) δH 8.29 (d, 1 H, J = 2.0 Hz), 8.16 (brs, 1H), 7.61 (brs, 1H), 7.22
(dd, 1H, J = 8.0 Hz, J = 1.4 Hz), 7.17 (t, 1H, J = 8.6 Hz), 7.04 (dd, 1H, J = 8.0 Hz, J = 1.4
Hz), 6.92 (t, 1H, J = 8.4 Hz).
3. Results and discussion
The compounds (I), (II) and (III) were prepared and characterized according to our previous
work [20,21], and their catalytic potential was assessed in the synthesis of formamides by N-
formylation of amines with formic acid (Scheme 2).
2-Chlorophenylamine was selected as the model substrate and the copper complex III as
the catalyst. To determine the optimum reaction conditions, the effects of different
parameters, such as the amounts of complex (III) and HCOOH, were studied. The results are
summarized in Table 1. Initially, the reaction was attempted in the absence of complex (III)
but it did not proceed and no products were formed even after 5 h at room temperature (Table
1, entry 1). Subsequently, to establish the importance of complex (III) and HCOOH in the
formation of N-(2-chlorophenyl) formamide, different amounts of these compounds were
used. The best result was obtained using 0.024 mmol (0.030 g) of complex (III) in the
5

presence of HCOOH (1.0 mmol) as the formylating agent at room temperature (Table 1, entry
5). The reaction was performed at ambient temperature in the presence of compounds (I) and
(II), with achieved product yield of 91 and 92% after 70 min of reaction time, respectively
(Table 1, entries 6 and 7). Next, the same reaction was carried out with various copper
catalyst salts, such as Cu(CH3COO)2∙H2O and Cu(NO3)2∙2.5H2O, which generated lower
product yields (Table 1, entries 8 and 9).
Table 1. Solvent-free N-formylation of 2-chlorophenylamine (0.5 mmol) with HCOOH (99%) catalysed by III
under different conditions at ambient temperature. a
Entry
HCOOH (mmol)
III (mmol)
III (0)
III (0.016)
III (0.024)
III (0.033)
Time
5 h
Yield %a
TONc
0
23.1
16.7
12.9
19.8
3.8
3.3
15
17
1
2
3
4
5
6
7
8
9
1.0
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
0
120 minb
120 minb
120 minb
60 min
70 min
70 min
165 minb
135 min
74
80
85
95
91
92
70
82
III (0.024)
I (0.12)
II (0.14)
Cu(CH3COO)2∙H2O (0.024)
Cu(NO3)2∙2.5H2O (0.024)
aYields are after work-up. bNot complete. cTurnover number (number of moles of product per mole of catalyst);
divide by 4 in order to obtain the value per mole of Cu (or per mole of ligand).
After the determination of the optimal reaction conditions, a range of substrates was
evaluated. The added solvent free reactions of various amines (aromatic, heterocyclic and
aliphatic) with HCOOH were carried out using catalysts (I), (II) and (III) at room
temperature. A wide variety of primary and secondary amines containing electron donating
and withdrawing substituents was converted to the corresponding formamides in high yields
and the results are shown in Table 2. According to the results obtained, column
chromatography or recrystallization are not required for the purification.
6

Table 2
N-Formylation of amines (0.5 mmol) with HCOOH (1.0 mmol) using 0.030 g of catalyst (0.12, 0.14 or 0.024
mmol of I, II or III, respectively), at different reaction times.
Entry
1
Amine
NH2
Product
NHCHO
Catalyst Time (min) Yield %a
TONb
I
70
70
60
90
91
92
3.8
3.3
19.2
II
III
2
I
II
III
60
60
50
92
92
93
3.8
3.3
19.4
NHCHO
NH2
Me
Me
3
4
5
III
40
94
19.6
MeO
NHCHO
MeO
NH2
I
II
III
70
70
60
91
92
95
3.8
3.3
19.8
NHCHO
NH2
Cl
Cl
I
II
III
55
55
50
92
90
93
3.8
3.2
19.4
Br
NHCHO
Br
NH2
6
III
III
85
92
19.2
16.7
NHCHO
NH2
OH
OH
7
8
75
80
NHMe
NCHO(Me)
CH2NHCHO
I
II
III
70
70
60
88
86
88
3.7
3.1
18.3
CH2NH2
9
III
65
89
18.5
O
NCHO
O
NH
aYields are after work-up. bTurnover number (number of moles of product per mole of catalyst); divide by 4 in
order to obtain the value per mole of Cu (or per mole of ligand).
The role of catalysts (I), (II) and (III) in the synthesis of formamides can be accounted for
by the proposed mechanism in Scheme 3. The catalyst acidic sites (Bronsted and Lewis
acids) present in the acid reaction medium can activate the carbonyl group of HCOOH via
interaction with its oxygen atom [6,28]. This enhances the electrophilic character of the
carbon atom of the carbonyl, making it more vulnerable to the nucleophilic attack by the
7

nitrogen of amines. This attack on the activated carbonyl group converts the amine into the
corresponding formamide.
O
O
-
Acidic sites of
(I), (II) and (III)
catalysts
OH
NRR'
H
R.T.
RR'NCHO
+
HCOOH
Solvent-Free
- H2O
H
OH
H
..
RR'NH
Scheme 3. Proposed mechanism for the preparation of formamides using catalysts (I), (II)
and (III).
The desired formamides were characterized by CHN, melting points, FTIR and NMR [7-
10]. The disappearance of the strong absorption band (NH2 stretching band) in the FTIR
spectrum of the amine and the appearance the one absorption band due to the carbonyl
stretching (N-formyl, C=O) in the range of 1640-1690 cm-1 confirmed the formation of the
formamides (Figures S1, S2 and S4). The FTIR spectra also showed a signal around 3200-
3400 cm-1, corresponding to the secondary NH stretching vibrations. However, this signal
was not observed in the FTIR spectra of the formamides from secondary amines such as N-
1
methylaniline (Figure S4). The H NMR spectra of the N-formamides showed the expected
two signals for the NH and aldehyde protons (Figure S3).
4. Conclusions
In summary, we have developed a solvent free synthetic method for the synthesis of
formamides at room temperature using arylhydrazones of malononitrile (I and II) and Cu(II)
complex (III) as effective catalysts. The catalysts used in the synthesis of formamides
showed good catalytic activity and the products were formed in good to excellent yields.
Using compounds (I) and (II) as catalysts, relatively similar performances with respect to
8

reaction time and yield for the preparation of formamides were obtained. In contrast with
compounds (I) and (II), the higher yield and lower reaction time can be seen in the synthesis
of formamides with the Cu(II) complex (III). However, the presence of copper (in the
tetranuclear catalyst III) does not improve considerably the process in terms of turnover
number per mole of copper (or of ligand). The present method has various advantages
including simple operation, mild reaction conditions, high yields, low catalyst load, and no
need for product purification. Further investigations on the application of these catalysts in
organic synthesis are in progress.
Acknowledgments
The support to this study by the University of Qom and Universidade de Lisboa is greatly
appreciated. This work was also supported by the Fundação para a Ciência e Tecnologia
(FCT), project UIDB/00100/2020 of Centro de Química Estrutural.
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Highlights:



N-Formylation of amines using arylhydrazones of malononitrile.
The reaction can be performed under solvent-free conditions at room temperature.
The products were obtained in excellent yields without of column chromatography.
11

All persons who have made substantial contributions to the work reported in the manuscript
(e.g., technical help, writing and editing assistance, general support), but who do not meet the
criteria for authorship, are named in the Acknowledgements and have given us their written
permission to be named. If we have not included an Acknowledgements, then that indicates
that we have not received substantial contributions from non-authors.
Best regards,
Mahmoud Nasrollahzadeh (on behalf of all the co-authors)
Graphical Abstract
N-Formylation of amines using arylhydrazones of malononitrile and a
Cu(II) complex under eco-friendly conditions at room temperature
Mahmoud Nasrollahzadeh,a,* Nayyereh Sadat Soheili Bidgoli,a Bruno G. M. Rocha,b,*
Armando J. L. Pombeiro,b and Kamran Mahmudov
*E-mail: mahmoudnasr81@gmail.com (M. Nasrollahzadeh).
*E-mail: bruno.g.m.rocha@tecnico.ulisboa.pt (B. G. M. Rocha)
12

O
R
R
I II III
( or
)
N
C
NH + HCOOH
solvent-free, r.t.
H
R'
R'
Na
O
N
C
C
O
O
S
N
N
N
CN
NC
H
N
N
Cu
Cu
O
C
N
O
N
O
O
N
H
OMe
MeO
MeO
N
H
I
NH
H
O
NC
N
C
C
Cu
O
O
O
N
N
H
N
C
H
O
N
O
Cu
N
N
MeO
C
N
II
N
NC
III
13