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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

by
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.
Molecules 2013, 18(10), 12488-12499; https://doi.org/10.3390/molecules181012488
Submission received: 28 August 2013 / Revised: 27 September 2013 / Accepted: 27 September 2013 / Published: 10 October 2013
(This article belongs to the Section Organic Chemistry)
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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.

Graphical Abstract

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 [1,2,3,4,5], 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 [6,7,8,9,10,11,12,13,14,15,16,17,18,19]. 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 double Strecker reaction from primary amines, and using excess amounts of both paraformaldehyde and cyanide sources, has also been developed [20,21,22]. 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 [26,27,28]. 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.
Table
Table 1. Examination of reaction conditions.
Table 1. Examination of reaction conditions.
Molecules 18 12488 i001
EntryCatalyst (mol%)Aldehyde aAdditiveTimeYield(%) b
(min)1a2a
1CuCl (5) + Cu(OTf)2 (5)PFA−−−1061ND
2CuCl (5) + Cu(OTf)2 (5)PFACaH21085ND
3CuCl (5) + Cu(OTf)2 (5)PFAt−BuOK1090ND
4CuCl (5) + Cu(OTf)2 (5)PFAK2CO310(99)ND
5CuCl (5) + Cu(OTf)2 (5)PFANa2CO31072ND
6CuCl (5) + Cu(OTf)2 (5)formalinK2CO310ND57
7CuCl (5) + Cu(OTf)2 (5)formalin−−−10ND(99)
8CuCl (10)PFAK2CO31065ND
9Cu(OTf)2 (10)PFAK2CO31043ND
10None cPFAK2CO312054ND
a PFA: paraformaldehyde, formalin: formaldehyde in 37wt% aqueous solution. b NMR (Isolated) yield. c Without both copper catalysts.
Table
Table 2. Selective synthesis of bis(cyanomethyl)methylenediamines 1 with paraformaldehyde a.
Table 2. Selective synthesis of bis(cyanomethyl)methylenediamines 1 with paraformaldehyde a.
Molecules 18 12488 i002
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.
Table
Table 3. Selective synthesis of N,N-bis(cyanomethyl)amines 2 with formalin a.
Table 3. Selective synthesis of N,N-bis(cyanomethyl)amines 2 with formalin a.
Molecules 18 12488 i003
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 coupling adducts. However, the reaction conditions with aromatic amines shown in Table 3 were not suitable for comparison.
Table
Table 4. Selective synthesis of bis(cyanomethyl)amines 3 and cyanomethylamines 4 with aromatic amines a.
Table 4. Selective synthesis of bis(cyanomethyl)amines 3 and cyanomethylamines 4 with aromatic amines a.
Molecules 18 12488 i004
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.
Molecules 18 12488 g001 550
Scheme 1. Conversion from bis(cyanomethyl)methylenediamines to bis(cyanomethyl)amine.
Scheme 1. Conversion from bis(cyanomethyl)methylenediamines to bis(cyanomethyl)amine.
Molecules 18 12488 g001
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 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.
Molecules 18 12488 g002 550
Scheme 2. Plausible reaction pathway for the multi−component coupling reaction.
Scheme 2. Plausible reaction pathway for the multi−component coupling reaction.
Molecules 18 12488 g002

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 noted. 1H-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.
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, J = 8.5 Hz), 7.23 (d, 2H, J = 8.5 Hz); 13C-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, J = 8.0 Hz), 7.20 (d, 2H, J = 8.0 Hz); 13C-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.
2,2'-[Methylenebis(benzylimino)]bisacetonitrile [26] (1c): 76 mg (42%); pale yellow oil; 1H-NMR (500 MHz, CDCl3) δ 3.50 (s, 2H), 3.58 (s, 4H), 3.79 (s, 4H), 7.35 (m, 10H); 13C-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.
2,2'-[Methylenebis(buthylimino)]bisacetonitrile [26] (1e): 96 mg (68%); 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), 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.
N-(4-Methoxybenzyl)-N,N-bis(cyanomethyl)amine (2a): 128 mg (99%); Pale yellow oil; 1H-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.
N-(4-Methylbenzyl)-N,N-bis(cyanomethyl)amine (2b): 119 mg (99%); Pale yellow oil; 1H-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, 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.
N-Benzyl-N,N-bis(cyanomethyl)amine [24] (2c): 107 mg (97%); Colorless oil; 1H-NMR (500 MHz, CDCl3) δ 3.60 (s, 4H), 3.79 (s, 2H), 7.33−7.39 (m, 5H); 13C-NMR (125 MHz, CDCl3) δ 41.5, 57.8, 114.2, 128.5, 128.8, 128.9, 134.7; MS(EI): m/z 185.
N-(2-Phenylethyl)-N,N-bis(cyanomethyl)amine (2d): 116 mg (97%); Pale yellow oil; 1H-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, J = 7.5 Hz), 3.61 (s, 4H); 13C-NMR (125 MHz, CDCl3) δ 13.7, 19.9, 29.0, 42.0, 53.4, 114.3; MS(EI): m/z 151.
N-Benzhydryl-N,N-bis(cyanomethyl)amine (2f): 94 mg (60%); Pale yellow oil; 1H-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, J = 7.5 Hz); 13C-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.
N-Cyclohexyl-N,N-bis(cyanomethyl)amine [34] (2g): 90 mg (99%); Pale yellow oil; 1H-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.
N-iso-Propyl-N,N-bis(cyanomethyl)amine [33] (2h): 81 mg (99%); pale yellow oil; 1H-NMR (300 MHz, CDCl3) δ 1.18 (d, 6H, J = 6.5 Hz), 3.05 (sept, 1H, J = 6.5 Hz), 3.69 (s, 4H); 13C-NMR (75 MHz, CDCl3) δ 19.7, 39.1, 52.8, 115.3; MS(EI): m/z 137.
N-(2-Hydroxyethyl)-N,N-bis(cyanomethyl)amine [35] (2i): 79 mg (95%); Pale yellow oil; 1H-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.
N-[4-(Methoxymethyl)phenyl]-N,N-bis(cyanomethyl)amine(2j'): 6% yield; Pale yellow oil; 1H-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.

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), 7.09 (d, 1H, J = 7.5 Hz), 7.18 (t, 1H, J = 7.5 Hz); 13C-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, J = 8.5 Hz); 13C-NMR (125 MHz, CDCl3) δ 32.1, 112.8. 116.3, 121.7 (q, 2JC−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 Hz), 8.08 (d, 1H, J = 9.0 Hz); 13C-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.

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: https://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.

References and Notes

  1. Rappoport, Z. The Chemistry of the Cyano Group; John Wiley & Sons Ltd.: New York, NY, USA, 1970. [Google Scholar]
  2. Lee, W.-C.; Sears, J.M.; Enow, R.A.; Eads, K.; Krogstad, D.A.; Frost, B.J. Hemilabile β-aminophosphine ligands derived from 1,3,5-triaza-7-phosphaadamantane: Application in aqueous ruthenium catalyzed nitrile hydration. Inorg. Chem. 2013, 52, 1737–1746. [Google Scholar] [CrossRef]
  3. Saavedra, J.Z.; Resendez, A.; Rovira, A.; Eagon, S.; Haddenham, D.; Singaram, B. Reaction of InCl3 with various reducing agents: InCl3–NaBH4-mediated reduction of aromatic and aliphatic nitriles to primary amines. J. Org. Chem. 2011, 77, 221–228. [Google Scholar]
  4. Addis, D.; Enthaler, S.; Junge, K.; Wendt, B.; Beller, M. Ruthenium N-heterocyclic carbene catalysts for selective reduction of nitriles to primary amines. Tetrahedron Lett. 2009, 50, 3654–3656. [Google Scholar] [CrossRef]
  5. Enthaler, S.; Addis, D.; Junge, K.; Erre, G.; Beller, M. A General and environmentally benign catalytic reduction of nitriles to primary amines. Chem. Eur. J. 2008, 14, 9491–9494. [Google Scholar] [CrossRef]
  6. Wang, J.; Liu, X.; Feng, X. Asymmetric Strecker reactions. Chem. Rev. 2011, 111, 6947–6983. [Google Scholar] [CrossRef]
  7. Gröger, H. Catalytic enantioselective Strecker reactions and analogous syntheses. Chem. Rev. 2003, 103, 2795–2828. [Google Scholar] [CrossRef]
  8. Enders, D.; Shilvock, J.P. Some recent applications of α-amino nitrile chemistry. Chem. Soc. Rev. 2000, 29, 359–373. [Google Scholar] [CrossRef]
  9. Nasreen, A. l-Proline catalyzed one pot synthesis of α-aminonitriles. Tetrahedron Lett. 2013, 54, 3797–3800. [Google Scholar] [CrossRef]
  10. Barbero, M.; Cadamuro, S.; Dughera, S.; Ghigo, G. o-Benzenedisulfonimide and its chiral derivative as Brønsted acids catalysts for one-pot three-component Strecker reaction. Synthetic and mechanistic aspects. Org. Biomol. Chem. 2012, 10, 4058–4068. [Google Scholar] [CrossRef]
  11. Rueping, M.; Zhu, S.; Koenigs, R.M. Visible-light photoredox catalyzed oxidative Strecker reaction. Chem. Commun. 2011, 47, 12709–12711. [Google Scholar] [CrossRef]
  12. Zhang, G.-W.; Zheng, D.-H.; Nie, J.; Wang, T.; Ma, J.-A. Brønsted acid-catalyzed efficient Strecker reaction of ketones, amines and trimethylsilyl cyanide. Org. Biomol. Chem. 2010, 8, 1399–1405. [Google Scholar] [CrossRef]
  13. Iwanami, K.; Seo, H.; Choi, J.-C.; Sakakura, T.; Yasuda, H. Al-MCM-41 catalyzed three-component Strecker-type synthesis of α-aminonitriles. Tetrahedron 2010, 66, 1898–1901. [Google Scholar] [CrossRef]
  14. Das, B.; Damodar, K.; Shashikanth, B.; Srinivas, Y.; Kalavathi, I. A mild and efficient catalytic Strecker reaction of N-alkoxycarbonylamino sulfones with trimethylsilyl cyanide using indium(III) chloride: A facile synthesis of α-aminonitriles. Synlett 2008, 3133–3136. [Google Scholar]
  15. Fontaine, P.; Chiaroni, A.; Masson, G.; Zhu, J. One-pot three-component synthesis of α-iminonitriles by IBX/TBAB-mediated oxidative Strecker reaction. Org. Lett. 2008, 10, 1509–1512. [Google Scholar] [CrossRef]
  16. Royer, L.; De, S.K.; Gibbs, R.A. Iodine as a novel and efficient reagent for the synthesis of α-aminonitriles by a three-component condensation of carbonyl compounds, amines, and trimethylsilyl cyanide. Tetrahedron Lett. 2005, 46, 4595–4597. [Google Scholar] [CrossRef]
  17. Martínez, R.; Ramón, D.J.; Yus, M. Catalyst-free multicomponent Strecker reaction in acetonitrile. Tetrahedron Lett. 2005, 46, 8471–8474. [Google Scholar] [CrossRef]
  18. Yadav, J.S.; Reddy, B.V.S.; Eeshwaraiah, B.; Srinivas, M. Montmorillonite KSF clay catalyzed one-pot synthesis of α-aminonitriles. Tetrahedron 2004, 60, 1767–1771. [Google Scholar] [CrossRef]
  19. De, S.K.; Gibbs, R.A. Bismuth trichloride catalyzed synthesis of α-aminonitriles. Tetrahedron Lett. 2004, 45, 7407–7408. [Google Scholar] [CrossRef]
  20. Dimroth, K.; Aurich, H.G. Zur Cyanmethylierung schwach basischer amine. Chem. Ber. 1965, 98, 3902–3906. [Google Scholar] [CrossRef]
  21. Yoda, R.; Matsushima, Y. Preparation of 2-aminooxyethyliminodiacetic acid, a bifunctional chelating agent for carbonyl labeling. Chem. Pharm. Bull. 1994, 42, 686–689. [Google Scholar] [CrossRef]
  22. Mowry, D.T. The preparation of nitriles. Chem. Rev. 1948, 42, 189–270. [Google Scholar] [CrossRef]
  23. Soleimani, E. Trimethylsilyl cyanide (TMSCN). Synlett 2007, 1625–1626. [Google Scholar] [CrossRef]
  24. Sakai, N.; Uchida, N.; Konakahara, T. Facile and selective synthesis of propargylic amines, and 1,6-diynes: one-pot three-component coupling reactions of alkynylsilanes, aldehydes, and amines by a cooperative catalytic system comprised of CuCl and Cu(OTf)2. Synlett 2008, 1515–1519. [Google Scholar]
  25. Chernyak, N.; Gevorgyan, V. General and efficient copper-catalyzed three-component coupling reaction towards imidazoheterocycles: One-pot synthesis of alpidem and zolpidem. Angew. Chem. Int. Ed. 2010, 49, 2743–2746. [Google Scholar] [CrossRef]
  26. Katritzky, A.R.; Pilarski, B.; Urogdi, L. Reactions of benzotriazole with formaldehyde and aliphatic primary amines: selective formation of 1:1:1, of 2:2:1, and of 2:3:2 adducts and a study of their reactions with nucleophiles. J. Chem. Soc.Perkin Trans. 1 1990, 541–547. [Google Scholar] [CrossRef]
  27. Bonfield, E.R.; Li, C.-J. Efficient ruthenium and copper cocatalyzed five-component coupling to form dipropargyl amines under mild conditions in water. Org. Biomol. Chem. 2007, 5, 435–437. [Google Scholar] [CrossRef]
  28. Sakaguchi, S.; Mizuta, T.; Furuwan, M.; Kubo, T.; Ishii, Y. Iridium-catalyzed coupling of simple primary or secondary amines, aldehydes and trimethylsilylacetylene: preparation of propargylic amines. Chem. Commun. 2004, 1638–1639. [Google Scholar]
  29. Paraformaldehyde (a powder state), which was purchased from different companies, WAKO (>94% purity) and TCI (>88% purity), was used. The crystalline or prilled state was not suitable for this reaction, due to insolubility in CH3CN.
  30. When the similar reaction was carried out with the amine (1 equiv), formaldehyde (1 equiv), and trimethylsilyl cyanide (1.5 equiv) under optimal conditions, the seven-component 1a was selectively obtained in a 94% yield.
  31. When the reaction time was prolonged to 2 h, the yield of the seven-component coupling adduct decreased to only 11%, instead, the Strecker-type product, the cyanomethylamine was obtained in a 70% yield.
  32. Larsen, S.D.; Grieco, P.A.; Fobare, W.F. Reactions of allylsilanes with simple iminium salts in water: A facile route to piperidines via a aminomethano desilylation-cyclization process. J. Am. Chem. Soc. 1986, 108, 3512–3513. [Google Scholar] [CrossRef]
  33. Gui-Hua, C.; Yun-Gui, P. The study on novel procedure for the preparation of EDTA and its mediate analogues. Guangzhou Chemical Industry 1 2009, 37, 65–66. [Google Scholar]
  34. Katritzky, A.R.; Latif, M.; Noble, G.; Harris, P. Preparation of N-alkyl, 2-substituted iminodiacetic acid derivatives. Synthesis 1990, 999–1000. [Google Scholar] [CrossRef]
  35. Song, B.; Recuber, J.; Ochs, C.; Hahn, F.E.; Lugger, T.; Orving, C. Effects of sequential replacement of –NH2 by –OH in the tripodal tetraamine tren on its acidity and metal ion coordinating properties. Inorg. Chem. 2001, 40, 1527–1535. [Google Scholar] [CrossRef]
  36. Dimroth, K.; Pintschovius, U. A new route to the synthesis of the pyrrole ring system. Justus Liebigs Ann. Chem. 1961, 639, 102–124. [Google Scholar] [CrossRef]
  37. Bailly, F.; Azaroual, N.; Bernier, J. Design, synthesis and glutathione peroxidase-like properties of ovothiol-derived diselenides. Bioorg. Med. Chem. 2003, 11, 4623–4630. [Google Scholar] [CrossRef]
  38. Michaelidou, S.S.; Koutentis, P.A. Microwave assisted synthesis of 3-aminoindole-2-carbonitriles from anthranilonitriles via N-unprotected 2-(cyanomethylamino)benzonitriles. Tetrahedron 2010, 66, 685–688. [Google Scholar] [CrossRef]
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MDPI and ACS Style

Sakai, N.; Takahashi, N.; Inoda, D.; Ikeda, R.; Konakahara, T. 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. Molecules 2013, 18, 12488-12499. https://doi.org/10.3390/molecules181012488

AMA Style

Sakai N, Takahashi N, Inoda D, Ikeda R, Konakahara T. 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. Molecules. 2013; 18(10):12488-12499. https://doi.org/10.3390/molecules181012488

Chicago/Turabian Style

Sakai, Norio, Nobuaki Takahashi, Daiki Inoda, Reiko Ikeda, and Takeo Konakahara. 2013. "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" Molecules 18, no. 10: 12488-12499. https://doi.org/10.3390/molecules181012488

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