Copper-Catalyzed three- Five- or seven-Component coupling reactions: The selective synthesis of cyanomethylamines, N,N-bis(cyanomethyl)amines and N,N'-bis(cyanomethyl)methylenediamines based on a strecker-type synthesis

Article abstract of DOI:10.3390/molecules181012488

We have demonstrated that a cooperative catalytic system comprised of CuCl and Cu(OTf)2 could be used to effectively catalyse the three-, five- and seven-component coupling reactions of aliphatic or aromatic amines, formaldehyde, and trimethylsilyl cyanide (TMSCN), and selectively produce in good yields the corresponding cyanomethylamines, N,N-bis(cyanomethyl)amines and N,N'-bis(cyanomethyl)methylenediamines.

Full text of DOI:10.3390/molecules181012488

Molecules 2013, 18, 12488-12499; doi:10.3390/molecules181012488
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Copper-Catalyzed Three- Five- or Seven-Component
Coupling Reactions: The Selective Synthesis of
Cyanomethylamines, N,N-Bis(Cyanomethyl)Amines and
N,N'-Bis(Cyanomethyl)Methylenediamines Based on a
Strecker-Type Synthesis
Norio Sakai *, Nobuaki Takahashi, Daiki Inoda, Reiko Ikeda and Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology,
Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
* Author to whom correspondence should be addressed; E-Mail: sakachem@rs.noda.tus.ac.jp;
Tel.: +81-4-7122-1092; Fax: +81-4-7123-9890.
Received: 28 August 2013; in revised form: 27 September 2013 / Accepted: 27 September 2013 /
Published: 10 October 2013
Abstract: We have demonstrated that a cooperative catalytic system comprised of CuCl
and Cu(OTf)2 could be used to effectively catalyse the three-, five- and seven-component
coupling reactions of aliphatic or aromatic amines, formaldehyde, and trimethylsilyl cyanide
(TMSCN), and selectively produce in good yields the corresponding cyanomethylamines,
N,N-bis(cyanomethyl)amines and N,N'-bis(cyanomethyl)methylenediamines.
Keywords: multi-component coupling; Strecker-type reaction; nitriles; copper
1. Introduction
Nitriles constitute a basic building block for natural products and biologically active substances and
have been used as useful precursors of other functional groups, such as amines, amides and carboxylic
acids [1–5], hence, the development of a facile and effective preparation of nitriles has attracted
considerable attention in the field of synthetic chemistry. Thus far, the main demand has been satisfied by
Strecker-type reactions using an amine, an aldehyde and an appropriate cyanide source [6–19].
However, the cyanide source used in conventional Strecker−type reactions is mainly limited to metal
cyanides, such as sodium or potassium cyanide. As an extension, the preparation of dinitriles via a

Molecules 2013, 18
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double Strecker reaction from primary amines, and using excess amounts of both paraformaldehyde
and cyanide sources, has also been developed [20–22]. In recent, the use of trimethylsilyl cyanide
(TMSCN), which is easy to handle and behaves as well as metal cyanides, has been developed and it
has been extensively used as a nitrile surrogate [23].
In this context, we reported that a cooperative catalytic system comprised of CuCl and Cu(OTf)2
catalyzes a five-component coupling reaction of amines, formaldehyde, and TMSCN producing a
dinitrile compound, a bis(cyanomethyl)amine derivative [24,25]. In the previous paper, the coupling
reaction examined was limited to one example using trimethylsilyl cyanide. Thus, during our ongoing
further extension on the five-component coupling reaction with the copper catalytic system and
trimethylsilyl cyanide, we newly found that either the properties of the formaldehyde that was used in
the reaction or the electronic effect of a substituent on an amine controlled a coupling mode of the
amines, formaldehyde, and TMSCN, and selectively produced three-, five- or seven-component
coupling products [26–28]. In this paper, we report on the detailed results of this unique multi-component
coupling reaction, which is based on a Strecker-type reaction.
2. Results and Discussion
As a model reaction, when the reaction of p-methoxybenzylamine, a solid paraformaldehyde [29]
(3 equiv.) and trimethylsilyl cyanide (TMSCN: 3 equiv.) was initially carried out with CuCl and Cu(OTf)2
in acetonitrile, an unexpected Strecker-type reaction occurred to produce the seven-component coupling
adduct, N,N'-bis(cyanomethyl)methylenediamine derivative 1a in a 61% yield within 10 min (entry 1
in Table 1) [30,31]. The structure of the amine 1a was determined by its spectroscopic data. In
addition, the use of a catalytic amount of a base promoted the seven−component coupling reaction,
improving the product yield (entries 2–5). In particular, potassium carbonate afforded the selective
formation of the seven−component coupling adduct 1a (entry 4). Potassium tert−butoxide also shows a
similar effect for the reaction (entry 5). It was noteworthy that when the reaction was performed with
formalin (37 wt% aqueous solution), in contrast, the five−component coupling adduct,
N,N-bis(cyanomethyl)amines 2a was obtained selectively (entry 6). When an aqueous solution of the
aldehyde that contained a much amount of monomer was used, the coupling form of three substrates was
switched. For a five-component coupling reaction, without a base, the yield of the amine was enhanced
to a nearly quantitative yield (entry 7). To show the utility of a cooperative catalytic system comprised
of CuCl and Cu(OTf)2, the single use (10 mol%) of each copper catalyst was examined. When the
reaction was conducted with either Cu(I) or Cu(II) under these conditions, it produced the
seven−component coupling adduct, and in both cases the yield was reduced (entries 8 and 9).
In addition, without both catalysts a substantial prolongation of the reaction time was observed (entry 10).
In general, the seven−coupling reaction with several aliphatic amines, paraformaldehyde and
TMSCN, was carried out under optimal conditions (Table 2). In most cases, the expected
seven−coupling reaction proceeded cleanly to selectively produce the corresponding
N,N'−bis(cyanomethyl)methylenediamine derivatives 1 in moderate to good yields, but, with the
exception of p−methylbenzyl amine, each reaction time was prolonged.

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Table 1. Examination of reaction conditions.
Time Yield (%) b
Catalyst
(mol%)
Entry
Aldehyde a
Additive
(min)
10
1a
61
2a
ND
ND
ND
ND
ND
57
CuCl (5) +
CuCl (5) +
CuCl (5) +
CuCl (5) +
CuCl (5) +
CuCl (5) +
CuCl (5) +
CuCl (10)
Cu(OTf)2 (10)
None c
1
2
3
4
5
6
7
8
9
PFA
PFA
−−−
CaH2
10
85
PFA
t−BuOK
K2CO3
Na2CO3
K2CO3
−−−
10
90
PFA
10
(99)
72
PFA
10
formalin
formalin
PFA
10
ND
ND
65
10
(99)
ND
ND
ND
K2CO3
K2CO3
K2CO3
10
PFA
10
43
10
PFA
120
54
a
b
PFA: paraformaldehyde, formalin: formaldehyde in 37wt% aqueous solution. NMR (Isolated) yield.
c Without both copper catalysts.
Table 2. Selective synthesis of bis(cyanomethyl)methylenediamines 1 with paraformaldehyde a.
a
Conditions: an amine (0.60 mmol), paraformaldehyde (1.80 mmol), TMSCN (1.80 mmol), Cu(OTf)2
(0.0300 mmol), CuCl (0.030 mmol) and K2CO3 (0.030 mmol) in CH3CN (0.6 mL).
Next, we performed selective preparations of a five-component coupling adduct with a formalin
solution (Table 3). When the reaction with primary aliphatic amines was conducted using the optimal
conditions shown in Table 1, the expected double Strecker products, the bis(cyanomethyl)amines 2b–e
was obtained selectively in excellent yields. The use of branched amines also produced the
corresponding amines 2f–h in good yields. It was noteworthy that this catalytic system successfully
accommodated coupling reactions using an aliphatic amine with a hydroxy group.

Molecules 2013, 18
Table 3. Selective synthesis of N,N-bis(cyanomethyl)amines 2 with formalin a.
12491
a
Conditions: an amine (0.60 mmol), formalin (37 wt% aqueous solution) (1.80 mmol), TMSCN
(1.80 mmol), Cu(OTf)2 (0.0300 mmol) and CuCl (0.030 mmol) in CH3CN (0.6 mL).
However, the catalytic system in acetonitrile could not be applied to the five−component coupling
reaction of aromatic amines (see the result for 2j). After many tests, the use of paraformaldehyde in
methanol effected the desired five-component coupling reaction for aromatic amines, selectively
affording the bis(cyanomethyl)amine derivatives 3a–d, but this tendency was true only for an aromatic
amine having an electron-donating group (Table 4). When the reaction was conducted with aniline, the
product yield was drastically reduced to less than 12%. Surprisingly, when the reaction was carried out
with an aromatic amine having a strong electron-withdrawing substituent, the typical Strecker-type
products cyanomethylamines 4a–c were obtained in good yields as sole products, even though the
reaction time was prolonged to 24 h. This is probably due to the fact that the nucleophilicity of the
formed secondary amine was drastically reduced by a strong electron-withdrawing group.
To understand the reaction pathway for the coupling reaction, several control experiments were
conducted (Scheme 1). When the isolated N,N'-bis(cyanomethyl)methylenediamine 1a was treated
with the conditions that selectively gave a double Strecker product, amine 1a was promptly and
completely converted to bis(cyanomethyl)amine 2a. Therefore, the result proved that a seven-component
adduct acted as a part of the precursor of a five-component coupling adduct. Simultaneously, the result
from this system showed that a retro-Mannich-type reaction had occurred. Also, when a similar
reaction was carried out with a mixture of solid paraformaldehyde and an amount of water equals to
that of the formalin solution used, the yield of the bis(cyanomethyl)amine was decreased to 45%.
Consequently, this implied that the structure of the formed amines depended on the properties of the
formaldehyde rather than on the presence of water. In other words, the use of formalin, which contains
a relatively large amount of monomer, tended to produce the selective formation of five-component
coupling adducts. In contrast, the employment of a solid paraformaldehyde, which was composed of a
polymer, under dehydrating conditions, preferentially tended to produce the seven-component

Molecules 2013, 18
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coupling adducts. However, the reaction conditions with aromatic amines shown in Table 3 were not
suitable for comparison.
Table 4. Selective synthesis of bis(cyanomethyl)amines 3 and cyanomethylamines 4 with
aromatic amines a.
a
Conditions: an amine (0.60 mmol), paraformaldehyde (1.80 mmol), TMSCN (1.80 mmol), Cu(OTf)2
(0.0300 mmol), CuCl (0.030 mmol) and K2CO3 (0.030 mmol) in CH3CN (0.6 mL) b Bis(cyanomethyl)amines
2j’ having a p−methoxymethylene group was obtained as a by−product.
Scheme 1. Conversion from bis(cyanomethyl)methylenediamines to bis(cyanomethyl)amine.
On the basis of the results, we present a plausible reaction pathway for the multi-component
coupling reaction as shown in Scheme 2. In the first step, amine A was formed from an amine,
formaldehyde, and TMSCN via a Strecker-type reaction. During this step, the role of copper triflate
was presumably that of the activation of formaldehyde and a consequent generation of N,O-hemiacetal.
Also, the copper chloride activated the trimethylsilyl cyanide to produce a cyanide anion. Then, two
molecules of cyanomethylamine A were condensed with formaldehyde to afford the corresponding
methylenediamine B, followed by a retro-Mannich reaction with the liberated water to form iminium

Molecules 2013, 18
12493
intermediate C and amine A [32]. Both amine A and iminium C were again reacted with TMSCN
and/or formaldehyde in the presence of copper catalysts to produce bis(cyanomethyl)amine D.
Scheme 2. Plausible reaction pathway for the multi−component coupling reaction.
3. Experimental
General
Column chromatography was performed using a silica gel. CH3CN was distilled from P2O5 and
dried over MS4A, respectively. Copper(I) and copper(II) salts were commercial available, and used
without a further purification. All reactions were carried out under a N2 atmosphere, unless otherwise
1
noted. H-NMR spectra were measured at 500 (or 300) MHz using TMS (tetramethylsilane) as an
internal standard. 13C-NMR spectra were measured at 125 (or 75) MHz using TMS or a center peak of
chloroform (77.0 ppm) as an internal standard. High−resolution mass spectra were measured using
NBA (3−nitrobenzylalcohol) as a matrix. A solid paraformaldehyde was purchased from Wako Pure
Chemical Ind. (purity > 95%) and TIC (purity > 88%), respectively. Known compounds were
identified by 1H-NMR and 13C-NMR by comparison with literature spectral data.
General procedure for the synthesis of N,N'-bis(cyanomethyl)methylenediamines
To a CH3CN solution (0.6 mL) in a screw-capped vial under a N2 atmosphere, an amine (0.60 mmol),
paraformaldehyde (1.80 mmol), trimethylsilyl cyanide (0.225 mL, 1.80 mmol), Cu(OTf)2 (10.8 mg,
0.0300 mmol), CuCl (3.0 mg, 0.030 mmol) and potassium carbonate (4.0 mg, 0.030 mmol) were
successively added, and the vial was sealed with a cap containing a PTFE septum. The reaction
mixture was stirred at room temperature. After the reaction, the mixture was directly subjected to SiO2
gel without the usual work-up, and was purified by flash column chromatography (hexane−AcOEt) to
give the corresponding amines.

Molecules 2013, 18
12494
2,2'-[Methylenebis(4-methoxybenzylimino)]bisacetonitrile (1a): 217 mg (99%); Pale yellow oil;
1H-NMR (500 MHz, CDCl3) δ 3.47 (s, 2H), 3.55 (s, 4H), 3.72 (s, 4H), 3.81 (s, 6H), 6.88 (d, 2H,
13
J = 8.5 Hz), 7.23 (d, 2H, J = 8.5 Hz); C-NMR (125 MHz, CDCl3) δ 38.6, 55.2, 55.3, 72.5, 114.1,
114.6, 128.2, 130.1, 159.4; MS(FAB): m/z 365 (M++H); HRMS(FAB): Calcd for C21H24N4O2:
365.1978, found 365.1974.
2,2'-[Methylenebis(4-methylbenzylimino)]bisacetonitrile (1b): 156 mg (78%); Pale yellow oil;
1H-NMR (500 MHz, CDCl3) δ 2.35 (s, 6H), 3.47 (s, 2H), 3.56 (s, 4H), 3.74 (s, 4H), 7.15 (d, 2H,
13
J = 8.0 Hz), 7.20 (d, 2H, J = 8.0 Hz); C-NMR (125 MHz, CDCl3) δ 21.1, 38.7, 55.5, 72.6, 114.6,
128.8, 129.4, 133.2, 137.7; MS(FAB): m/z 333 (M++H); HRMS(FAB): Calcd for C21H24N4: 333.2079,
found 333.2051.
1
2,2'-[Methylenebis(benzylimino)]bisacetonitrile [26] (1c): 76 mg (42%); pale yellow oil; H-NMR
13
(500 MHz, CDCl3) δ 3.50 (s, 2H), 3.58 (s, 4H), 3.79 (s, 4H), 7.35 (m, 10H); C-NMR (125 MHz,
CDCl3) δ 38.9, 55.8, 72.6, 114.6, 128.0, 128.8, 128.9, 136.2.
2,2'-[Methylenebis(2-phenylethyllimino)]bisacetonitrile (1d): 145 mg (73%); Pale yellow oil;
1H-NMR (500 MHz, CDCl3) δ 2.74 (t, 4H, J = 7.0 Hz), 2.85 (t, 4H, J = 7.0 Hz), 3.28 (s, 2H), 3.44
(s, 4H), 7.15 (d, 4H, J = 6.5 Hz), 7.21 (t, 2H, J = 6.5 Hz), 7.29 (t, 4H, J = 6.5 Hz); 13C-NMR
(125 MHz, CDCl3) δ 33.7, 39.0, 52.6, 73.0, 115.0, 126.4, 128.5, 128.5, 139.0; MS(FAB): m/z 331
(M+−H); HRMS(FAB): Calcd for C21H23N4: 331.1923 (M+−H), found 331.1917.
1
2,2'-[Methylenebis(buthylimino)]bisacetonitrile [26] (1e): 96 mg (68%); Pale yellow oil; H-NMR
(500 MHz, CDCl3) δ 2.74 (t, 4H, J = 7.0 Hz), 2.85 (t, 4H, J = 7.0 Hz), 3.28 (s, 2H), 3.44 (s, 4H), 7.15 (d,
4H), 7.21 (t, 2H), 7.29 (t, 4H); 13C-NMR (125 MHz, CDCl3) δ 13.8, 20.2, 29.3, 39.2, 51.4, 72.9, 115.0.
General procedure for the synthesis of N,N-bis(cyanomethyl)amines using an aliphatic amine
To a CH3CN solution (0.6 mL) in a screw-capped vial under a N2 atmosphere, an aliphatic amine
(0.60 mmol), a formaldehyde aqueous solution (0.135 mL, 1.80 mmol), trimethylsilyl cyanide
(0.225 mL, 1.80 mmol), Cu(OTf)2 (10.8 mg, 0.0300 mmol) and CuCl (3.0 mg, 0.030 mmol) was
successively added, and the vial was sealed with a cap containing a PTFE septum. The reaction
mixture was stirred at room temperature. After the reaction, the mixture was directly subjected to SiO2
gel without the usual extraction, and was purified by flash column chromatography (hexane-AcOEt) to
give the corresponding N,N-bis(cyanomethyl)amines.
1
N-(4-Methoxybenzyl)-N,N-bis(cyanomethyl)amine (2a): 128 mg (99%); Pale yellow oil; H-NMR
(500 MHz, CDCl3) δ 3.58 (s, 4H), 3.73 (s, 2H), 3.82 (s, 3H), 6.90 (d, 2H, J = 8.5 Hz), 7.26 (d, 2H,
J = 8.5 Hz); 13C-NMR (125 MHz, CDCl3) δ 41.4, 55.3, 57.5, 114.2, 114.4, 126.7, 130.4, 159.8;
MS(EI): m/z 215; HRMS(FAB): Calcd for C12H14N3O: 216.1137, found 216.1145.
1
N-(4-Methylbenzyl)-N,N-bis(cyanomethyl)amine (2b): 119 mg (99%); Pale yellow oil; H-NMR
(500 MHz, CDCl3) δ 2.36 (s, 3H), 3.58 (s, 4H), 3.74 (s, 2H), 7.18 (d, 2H, J = 8.0 Hz) 7.22 (d, 2H,

Molecules 2013, 18
12495
J = 8.0 Hz); 13C-NMR (125 MHz, CDCl3) δ 21.1, 41.5, 57.7, 114.2, 129.0, 129.6, 131.7, 138.5;
MS(EI): m/z 199; HRMS(FAB): Calcd for C12H14N3: 200.1188, found 200.1190.
1
N-Benzyl-N,N-bis(cyanomethyl)amine [24] (2c): 107 mg (97%); Colorless oil; H-NMR (500 MHz,
13
CDCl3) δ 3.60 (s, 4H), 3.79 (s, 2H), 7.33−7.39 (m, 5H); C-NMR (125 MHz, CDCl3) δ 41.5, 57.8,
114.2, 128.5, 128.8, 128.9, 134.7; MS(EI): m/z 185.
1
N-(2-Phenylethyl)-N,N-bis(cyanomethyl)amine (2d): 116 mg (97%); Pale yellow oil; H-NMR
(500 MHz, CDCl3) δ 2.80 (t, 2H, J = 7.5 Hz), 2.91 (t, 2H, J = 7.5 Hz), 3.60 (s, 4H), 7.19 (d, 2H, J = 7.5
Hz), 7.24 (t, 1H, J = 7.5 Hz), 7.31 (t, 2H, J = 7.5 Hz); 13C-NMR (125 MHz, CDCl3) δ 33.5, 42.1, 54.8,
114.2, 126.7, 128.5, 128.6, 137.9; MS(EI): m/z 198 (M+−H); HRMS(FAB): Calcd for C12H12N3:
198.1031 (M+−H), found 198.1014.
N-Butyl-N,N-bis(cyanomethyl)amine [33] (2e): 90 mg (99%); Pale yellow oil; 1H-NMR (500 MHz, CDCl3)
δ 0.94 (t, 3H, J = 7.5 Hz), 1.37 (sext, 2H, J = 7.5 Hz), 1.49 (quint, 2H, J = 7.5 Hz), 2.65 (t, 2H,
13
J = 7.5 Hz), 3.61 (s, 4H); C-NMR (125 MHz, CDCl3) δ 13.7, 19.9, 29.0, 42.0, 53.4, 114.3; MS(EI):
m/z 151.
1
N-Benzhydryl-N,N-bis(cyanomethyl)amine (2f): 94 mg (60%); Pale yellow oil; H-NMR (500 MHz,
CDCl3) δ 3.64 (s, 4H), 4.67 (s, 1H), 7.27 (t, 2H, J = 7.5 Hz), 7.34 (t, 4H, J = 7.5 Hz), 7.47 (d, 4H,
13
J = 7.5 Hz); C-NMR (125 MHz, CDCl3) δ 40.6, 71.8, 114.4, 127.4, 128.5, 129.4, 139.4; MS(FAB):
m/z 262 (M++H); HRMS(FAB): Calcd for C17H16N3: 262.1344, found 262.1353.
1
N-Cyclohexyl-N,N-bis(cyanomethyl)amine [34] (2g): 90 mg (99%); Pale yellow oil; H-NMR
(500 MHz, CDCl3) δ 1.17 (m, 1H), 1.29 (m, 4H), 1.65 (m, 1H), 1.81 (m, 2H,), 1.93 (m, 2H), 2.63 (m, 1H),
3.72 (s, 1H); 13C-NMR (125 MHz, CDCl3) δ 24.8, 25.3, 29.8, 39.2, 60.3, 115.4; MS(EI): m/z 151.
1
N-iso-Propyl-N,N-bis(cyanomethyl)amine [33] (2h): 81 mg (99%); pale yellow oil; H-NMR
13
(300 MHz, CDCl3) δ 1.18 (d, 6H, J = 6.5 Hz), 3.05 (sept, 1H, J = 6.5 Hz), 3.69 (s, 4H); C-NMR
(75 MHz, CDCl3) δ 19.7, 39.1, 52.8, 115.3; MS(EI): m/z 137.
1
N-(2-Hydroxyethyl)-N,N-bis(cyanomethyl)amine [35] (2i): 79 mg (95%); Pale yellow oil; H-NMR
(500 MHz, CDCl3) δ 2.02 (brs, 1H), 2.88 (t, 2H, J = 5.0 Hz), 3.75 (s, 4H), 3.80 (t, 2H, J = 5.0 Hz);
13C-NMR (125 MHz, CDCl3) δ 42.9, 53.1, 66.1, 114.5; MS(EI): m/z 139.
N-Phenyl-N,N-bis(cyanomethyl)amine [36] (2j): 37 mg (36%); pale yellow solid; mp. 159–160°C
1H-NMR (500 MHz, CDCl3) δ 4.24 (s, 3H), 7.00 (d, 2H, J = 7.5 Hz), 7.11 (t, 1H, J = 7.5 Hz) , 7.39 (t,
1H, J = 7.5 Hz); 13C-NMR (125 MHz, CDCl3) δ 41.0, 114.6, 117.2, 123.4, 130.0, 145.4; MS(EI): m/z 171.
1
N-[4-(Methoxymethyl)phenyl]-N,N-bis(cyanomethyl)amine (2j'): 6% yield; Pale yellow oil; H-NMR
(500 MHz, CDCl3) δ 3.39 (s, 3H), 4.24 (s, 4H), 4.42 (s, 2H), 6.97 (d, 2H, J = 9.0 Hz), 7.35 (d, 2H,
J = 9.0 Hz); 13C-NMR (125 MHz, CDCl3) δ 41.0, 58.1, 73.9, 114.5, 117.1, 129.5, 133.8, 144.9;
HRMS(FAB): Calcd for C12H13N3O: 215.1059, found 215.1032.

Molecules 2013, 18
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General procedure for the synthesis of N,N-bis(cyanomethyl)amines using an aromatic amine
To a CH3CN solution (0.6 mL) in a screw-capped vial under a N2 atmosphere, an amine
(0.60 mmol), paraformaldehyde (1.80 mmol), trimethylsilyl cyanide (0.225 mL, 1.80 mmol), Cu(OTf)2
(10.8 mg, 0.0300 mmol), CuCl (3.0 mg, 0.030 mmol) and potassium carbonate (4.0 mg, 0.030 mmol)
were successively added, and the vial was sealed with a cap containing a PTFE septum. The reaction
mixture was stirred at room temperature. After the reaction, the mixture was directly subjected to SiO2
gel without the usual work-up, and was purified by flash column chromatography (hexane-AcOEt) to
give the corresponding amines.
N-(4-Methoxyphenyl)-N,N-bis(cyanomethyl)amine [24] (3a): 119 mg (99%); white solid; mp 114–115 °C;
1H-NMR (500 MHz, CDCl3) δ 3.80 (s, 3H), 4.13 (s, 4H), 6.91 (d, 2H, J = 9.0 Hz), 7.04 (d, 2H, J = 9.0 Hz);
13C-NMR (125 MHz, CDCl3) δ 42.2, 55.5, 114.7, 115.1, 121.0, 139.3, 156.8; MS(EI): m/z 201.
N-(2-Methoxyphenyl)-N,N-bis(cyanomethyl)amine (3b): 119 mg (99%); White solid; mp 61–62 °C;
1H-NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 4.18 (s, 4H), 6.94 (d, 1H, J = 7.5 Hz), 6.97 (t, 1H, J = 7.5 Hz),
13
7.09 (d, 1H, J = 7.5 Hz), 7.18 (t, 1H, J = 7.5 Hz); C-NMR (125 MHz, CDCl3) δ 41.2, 55.6, 112.0,
115.1, 121.3, 121.7, 126.7, 134.7, 152.9; MS(EI): m/z 201; HRMS(FAB): Calcd for C11H11N3O:
201.0902, found 201.0916.
N-(4-Methylphenyl)-N,N-bis(cyanomethyl)amine [36] (3c): 100 mg (90%); Yellow solid; mp 119–120 °C;
1H-NMR (500 MHz, CDCl3) δ 2.32 (s, 3H), 4.18 (s, 4H), 6.91 (d, 2H, J = 8.0 Hz), 7.17 (d, 2H, J = 8.0
Hz); 13C-NMR (125 MHz, CDCl3) δ 20.5, 41.3, 114.7, 117.8, 130.4, 133.5, 143.2; MS(EI): m/z 185.
N-(3,4-Dimethylphenyl)-N,N-bis(cyanomethyl)amine (3d): 105 mg (88%); white solid; mp 136–137 °C;
1H-NMR (500 MHz, CDCl3) δ 2.22 (s, 3H), 2.27 (s, 3H), 4.18 (s, 4H), 6.74 (d, 1H, J = 8.0 Hz), 7.79
(s, 1H), 7.11(d, 1H, J = 8.0 Hz); 13C-NMR (125 MHz, CDCl3) δ 18.9, 20.1, 41.3, 114.7, 115.2, 119.3,
130.8, 132.2, 138.3, 143.6; MS(EI): m/z 199: HRMS(FAB): Calcd for C12H13N3:199.1109, found
199.1082.
N-[4-(Trifluoromethyl)phenyl]-N-(cyanomethyl)amine [37] (4a): 92 mg (77%); White solid; mp 106 °C;
1H-NMR (500 MHz, CDCl3) δ 4.13 (s, 2H), 4.39 (brs, 1H), 6.72 (d, 2H, J = 8.5 Hz), 7.50 (d, 2H,
13
2
J = 8.5 Hz); C-NMR (125 MHz, CDCl3) δ 32.1, 112.8. 116.3, 121.7 (q, JC−F = 32.6 Hz), 124.5 (q,
1JC−F = 271.2 Hz), 126.9 (q, 3JC−F = 3.4 Hz), 147.6; MS(EI): m/z 200.
N-(4-Nitrophenyl)-N-(cyanomethyl)amine [20] (4b): 90 mg (85%); Yellow solid; mp 112–113 °C;
1H-NMR (500 MHz, DMSO−d6) δ 4.44 (d, 2H, J = 4.5Hz), 6.81 (d, 2H, J = 9.0 Hz), 7.6 (t, 1H, J = 4.5
13
Hz), 8.08 (d, 1H, J = 9.0 Hz); C-NMR (125 MHz, DMSO−d6) δ 30.9, 112.0, 117.6, 126.1, 137.9,
152.6; MS(EI): m/z 177.
N-(2-cyanophenyl)-N-(cyanomethyl)amine [38] (4c): 75 mg (80%); White solid; mp 95–96 °C;
1H-NMR (500 MHz, CDCl3) δ 4.20 (d, 2H, J = 6.5 Hz), 5.21(brs, 1H), 6.80 (d, 1H, J = 7.5 Hz), 6.87
(t, 1H, J = 7.5 Hz), 7.48 (d, 1H, J = 7.5 Hz), 7.52 (t, 1H, J = 7.5 Hz); 13C-NMR (125 MHz, CDCl3) δ
31.6, 97.6, 111.0, 115.9, 117.1, 119.1, 133.1, 134.6, 147.6.

Molecules 2013, 18
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4. Conclusions
We have demonstrated that a cooperative catalytic system comprised of CuCl and Cu(OTf)2
effectively catalyzes a three-, five- or seven-component coupling reaction of aliphatic amines,
formaldehyde, and TMSCN under neutral or basic conditions to produce cyanomethylamines,
N,N-bis(cyanomethyl)amines, and N,N'-bis(cyanomethyl)methylenediamines, respectively. We also
have found that a seven-component adduct functioned as a part of the precursor of a five-component
coupling adduct in a multi-component coupling reaction series.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/10/12488/s1.
Acknowledgments
This work was partially supported by a grant from the Japan Private School Promotion Foundation
supported by MEXT.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Not available
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