F.M. Moghaddam et al.
Catalysis Communications 149 (2021) 106211
Thus, the optimized reaction conditions for
α-cyanation of N,N-
Table 2
Scope of the oxidative
α
-cyanation catalyzed by CoCuFe2O4.a
Product
dimethylaniline are CoCuFe2O4 (5 mol%) in MeOH/HOAc using NaCN
as cyanide source and TBHP as oxidant at room temperature for 2.5 h
(Table 1, entry 15).
Entry
Reactant
Yieldb(%)
89
1
To generalize the protocol developed, a variety of tertiary/secondary
amines were used as the substrate for oxidative cyanation under opti-
mized reaction conditions. The results of these experiments are pre-
sented in Table 2.
2
3
88
85
Results showed that aromatic substrates bearing electron-donating
groups were found to be more reactive as compared to the substrates
having electron-withdrawing groups.
For
N-methylisatin,
N-methylimidazole,
N-ethyl-N-phenyl-
benzamide, and 4-(4-methyl-thiobenzoyl)-morpholine, the starting
materials remained intact even after 24 h and under temperatures up to
50 ◦C. This observation proved that the presence of free ion pair of ni-
trogen atoms is vital for this transformation, and in substrates whose ion
pair of nitrogen is involved in the resonance, the corresponding amino
nitrile cannot be formed. The reactions of cyclic amine such as piperi-
4
5
6
77
71
29
dine derivative proceeded well and afforded the corresponding
nitriles in good yields.
α-amino
Steric hindrance also seems to have an effect on the results. For
example, the reaction of bulky tribenzylamine afforded the expected
product in 47% yield (Table 2, entry 11).
N,N-Dimethylbenzylamine, as an unsymmetrical amine, underwent
a regioselective oxidative cyanation in the methyl group rather than in
the methylene carbon of the benzyl group to furnish the desired product
in 53% yield (Table 2, entry 10).
7
41
Comparing entries 1 and 13 revealed that tertiary amines are more
–
reactive toward this C C coupling rather than secondary amines.
It is worth mentioning that in all cases, the
α
-C(sp3)–H bond of amine
8
9
86
62
is cleaved and functionalized under the present reaction conditions.
To demonstrate the applicability of this catalytic system, we shifted
our focus toward the late-stage functionalization of pharmaceutical
molecules (Table 3). For this purpose, biologically active molecules such
as nicotine as an alkaloid and two known drugs (repaglinide and riva-
stigmine) were selected.
Repaglinide, a drug with an unprotected acid functionality, provided
the Cαꢀ H cyanation product in the highest yield in this series.
10
11
53
47
For nicotine, a molecule with different available α-protons for sub-
–
stitution, C H cyanation selectively occurred at the pyrrolidine ring
and no methyl cyanation was observed. In fact, the reaction took place at
the less hindered carbon.
Rivastigmine as an aliphatic acyclic tertiary amine underwent the
Cαꢀ H cyanation in relatively low yields under our conditions. In fact,
introducing the CN unit on drug molecules could develop the drug
biological functionality [3]. Nitrile is a strong hydrogen bond acceptor
and may improve solubility and alter the biological function of the
molecule by modulating the interactions with a diverse range of
bioactive receptors. As the nitrile segment is smaller than bromine and
iodine, it has better contact with amino acids locating at the active site.
Apart from the mentioned features, the nitrile group is a key component
for molecular recognition and could be transferred into other valuable
and practical functional groups.
12
80
13
14
78
49
We then focused on demonstrating the synthetic utility of the cata-
lytic system on a large scale. The scalability of the procedure was
explored by the reaction of N,N-dimethylaniline and NaCN under the
optimized reaction conditions on 10 mmol scale (Scheme 2). Results
indicate that CoCuFe2O4 catalytic system has the potential to be
a
Reaction conditions: substrate (0.5 mmol), NaCN (0.6 mmol), TBHP (1.25
mmol), CH3OH/HOAc (2 mL), CoCuFe2O4 (5 mol%), at room temperature, 2.5 h.
employed for large scale synthesis of α-amino nitriles in high yields.
In terms of industrial applications, the recyclability of the catalyst is
a very important factor. To check the reusability of the catalyst, the
oxidative cyanation of N,N-dimethylaniline was investigated under the
optimized reaction conditions. At the end of the reaction, the catalyst
was easily separated by an external magnet, washed with EtOH, dried,
and reused for consecutive reaction runs. This process was repeated 5
times, and each time, the isolated yield was calculated exactly. Fig. 1
b
Isolated yield.
clearly indicates the efficient recycling of the catalyst without any sig-
nificant loss in catalytic activity. Furthermore, to ascertain the leaching
of the catalyst, the filtrates were subjected to ICP analysis; no metal
could be observed, therefore establishing that the catalyst is truly a
4