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Development of one-pot three component reaction for the synthesis of N′-aryl-N-cyanoformamidines, essential precursors of formamidine pesticides family
⁎Corresponding authors. Tel.: +39 0984492043. denino@unical.it (Antonio De Nino), maiuolo@unical.it (Loredana Maiuolo)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Efficient one-pot three component reaction of aniline derivatives with cyanoamide and triethyl orthoformate at reflux in toluene affords N′-aryl-N-cyanoformamidines in high yields just by the distillation of the azeotrope toluene/ethyl alcohol. Labelled d9-Amitraz is prepared by the application of this procedure in the synthesis of formamidine pesticides family.
Keywords
Cyanoformamidines
Pesticides
One-pot reaction
Labelled compounds
1 Introduction
The usual procedure for the synthesis of organic compounds is the stepwise formation of the individual bonds in the target molecule. However, it would be much more efficient if one could form several bonds in one sequence without isolating the intermediates, changing the reaction conditions, or adding reagents (Tietze and Beifuss, 1993; Waldmann, 1995; Hall, 1994). Thus, multicomponent condensation was an active field in the research of organic reactions because it can readily construct complicated heterocyclic scaffolds (Yu et al., 2011; Dondoni and Massi, 2006). It is obvious that the one-pot multicomponent reactions represent a possible instrument to perform a near ideal synthesis building-up complex molecules with maximum simplicity and brevity (Hudlicky, 1996), minimizing the waste production, and allowing an ecologically and economically favorable process.
Generally the preparation of aromatic cyanoformamidines is realized, either in two steps by the isolation of cyanoformimidates and subsequent substitution with aromatic amines (Cereda et al., 1986) or, in few examples, in a one-pot reaction without solvent in 39–96 % yields (Schaefer and Gewald, 1976). Now, herein we report an extended and improved three component reaction involving commercially available aromatic primary amines 1 with triethyl orthoformate 2 and cyanoamide 3 in toluene to provide N′-aryl-N-cyanoformamidines 4 by a one-pot method (Scheme 1).
General synthesis of aromatic cyanoformamidines.
Cyanoformamidines are important intermediates for the synthesis of asymmetric formamidines that have been extensively checked as pesticides (Leung et al., 1999; Nakayama et al., 1997; Baxter and Barker, 1999; Moss, 1996; Beeman and Matsumura, 1973) (i.e. Amitraz, Chlordimephorm, Formethanate) and as pharmacological agents (Gall et al., 1988; Donetti et al., 1984; Scott et al., 1983). In fact, unlike the formamidines which easily hydrolyze, the presence of a nitrile group on the structure of the cyanoformamidines makes these compounds more stable and increases the electrophilicity of the formyl carbon to nucleophilic attack for further transformations. For example N′-aryl-N-cyanoformamidines were converted to a variety of N′-aryl-N-alkylformamidines with excess of alkyl or dialkylamines (Yu et al., 2011; Dondoni and Massi, 2006) and in 2-substituted 6-aryl-1,3-oxazin-4-ones by reaction with aroylketenes (Nekrasov, 2001).
2 Results and discussion
In our effort to develop a one pot synthesis of N′-aryl-N-cyanoformamidines 4, from primary amines 1, triethyl orthoformate 2 and cyanoamide 3 by the sequential nucleophilic attack of amine and cyanoamide to the triethyl orthoformate we examined several reaction conditions. We chose toluene as the solvent system because it forms an azeotrope with the ethanol that can be removed from the system by distillation, allowing rapid and complete transformation of the reagents (entry 5, Table 1).
Entry
Amine
Solvent
Time (min)
Temp
Yielda (%)
1
Aniline
THF
60
Reflux
52
2
Aniline
Dioxane
60
Reflux
55
3
Aniline
Acetonitrile
60
Reflux
50
4b
Aniline
Toluene
60
Reflux
77
5c
Aniline
Toluene
30
Reflux
96
To explore the feasibility, scope and limitations of this one-pot approach, a number of amines 1 were utilized and the results are summarized in Table 2. In almost all cases, the cyanoformamidine formation was quick and in good yields but when aliphatic amines were utilized and the nucleophilicity was comparable with the cyanoamide, the reactions were unselective, the main product was a mixture of double addition of cyanamide or aliphatic amine and only traces of cyanoformamidine were obtained (entries 24–25, Table 2).
Entry
Ar
Product
Yielda (%)
1
C6H5
4a
96
2
4-MeC6H4
4b
95
3
2-i-PrC6H4
4c
87
4
4-i-PrC6H4
4d
90
5
2,4-Me2C6H3
4e
97
6
3,4-Me2C6H3
4f
97
7
2-MeOC6H4
4g
96
8
3-MeOC6H4
4h
93
9
4-MeOC6H4
4i
87
10
2,4-(MeO)2C6H3
4j
89
11
2,5-(MeO)2C6H3
4k
91
12
2-ClC6H4
4l
76
13
3-ClC6H4
4m
84
14
4-ClC6H4
4n
81
15
2,3-Cl2C6H4
4o
75
16
2,4-Cl2C6H4
4p
88
17
2,5-Cl2C6H4
4q
77
18
2-BrC6H4
4r
71
19
3-BrC6H4
4s
77
20
4-BrC6H4
4t
79
24
Cyclohexyl
4u
8b
25
Butyl
4v
10b
As shown in Table 2, this protocol can be excellently applied on aromatic amines with either electron-withdrawing groups (such as halogens) or electron-donating groups (such as alkyl or alkoxyl groups). In general, the reaction is complete when the azeotrope is totally distilled off (30 min) at the temperature of reflux (76.5 °C), the N′-aryl-N-cyanoformamidines 4 crystallizes out and is isolated in a pure form simply by filtration.
In the past years, our group has developed original and accurate analytical method for assay of microcomponents (De Nino et al., 2005; Di Donna et al., 2009), compounds for the food sophistication (Di Donna et al., 2004; Sindona et al., 2009; De Nino et al., 2007) and pesticides (Maiuolo et al., 2009). In this context and to further extend the utility of the procedure, we report a convenient access to d9-1,5-di-(2,4-dimethylphenyl)-3-methyl-1,3,5-triazapenta-1,4-diene (d9-Amitraz) (Scheme 2). Other acaricide-insecticides, of the formamidines family can be prepared using the same procedure with different cyanoformamidines. Amitraz (Leung et al., 1999; Baxter and Barker, 1999; Nakayama et al., 1997; Shin and Hsu, 1994; Queirozneto et al., 1994) is a triazapentadiene compound, a member of the formamidine class chemical family. It is used to control red spider mites, leaf miners, scale insects, and aphids (Cozzani and Di Pietrogiacomo, 1989). On animals, it is used to control ticks, mites, lice and other pests (Harrison et al., 1972; Tolim, 1994; Tudek et al., 1988).
Synthetic route to d9-Amitraz 7.
In the synthetic procedure the N′-(2,4-dimethylphenyl)-N-cyanoformamidine 4e undergo nucleophilic attach by methylamine on formyl carbon and, by the elimination of cyanoamide hydrochloride, furnish an asymmetrical formamidine 6, that in toluene and in the presence of copper(I) oxide attach the labelled isocyanide 5 to give d9-Amitraz 7. This product could be employed for absolute quantitative determinations in biological matrices, using the synthetic labelled analogue as an internal standard.
Labelled isocyanide 5 was prepared according to the following Scheme 3.
Synthesis of labelled isocyanide 5.
3 Experimental
All solvents and reagents were obtained commercially and used without further purification. 1H NMR spectra were recorded on a 300 MHz Bruker instrument in the DMSO-d6 solvents except for the compounds 6 and 7 (CDCl3). Chemical shifts are given in ppm, and coupling constants are in Hertz. In solution the cyanoformamidines exist in two tautomeric forms2 (Scheme 4) giving NMR spectra complicated by the presence of more signals in comparison with those expected. Melting points are uncorrected and were determined with a Kofler hot stage. Elemental analyses (C, H, and N) were obtained using a Flash 2000, Thermo Fisher Scientific elemental analyzer.
Equilibrium of tautomeric forms.
3.1 General procedure for one-pot synthesis of cyanoformamidines 4
A mixture of the primary amine (5 mmol), triethyl orthoformate (5 mmol) and cyanoamide (7.5 mmol) in toluene (7.5 mL) was stirred at 75–80 °C in a round-bottom flask fitted with a distillation apparatus until the azeotrope (76.5 °C) toluene/ethanol had been completely removed (30 min). After completion the reaction mixture was cooled, the product filtered and crystallized from ethanol.
3.1.1 N′-phenyl-N-cyanoformamidine 4a
White solid; yield 96%; mp 142–143 °C (lit.3 144–145 °C); 1H NMR (DMSO-d6) 11.19 (bs, 1H, NH) 9.12–8.53, (bs, s, 1H, CH), 7.75–6.98 (m, 5H, Ar); 13C NMR (DMSO-d6) 163.5,161.2, 137.8, 136.9, 129.4, 128.8, 125.3, 124.9, 121.1, 117.9. Anal. calcd for C8H7N3: C, 66.19 H, 4.86 N, 28.95. Found: C, 66.25 H, 4.82 N, 28.93.
3.1.2 N′-4-tolyl-N-cyanoformamidine 4b
White solid, yield 95%; mp 182–183 °C (lit.3 183–185 °C); 1H NMR (DMSO-d6) 11.25–10.85 (2bd, J1 = 11.6 Hz, J2 = 4.9 Hz, 1H, NH) 8.47, 9.04 (2d, J1 = 11.6 Hz, J2 = 4.9 Hz, 1H, CH), 6.94–7.63 (m, 4H, Ar), 2.26, 2.28 (2s, 3H, CH3); 13C NMR (DMSO-d6) 162.64, 160.13, 134.60, 133.97, 133.80, 133.54, 129.08, 128.54, 120.40, 117.29, 19.69, 19.52. Anal. calcd for C9H9N3: C, 67.90 H, 5.70 N, 26.40. Found: C, 67.86 H, 5.72 N, 26.42.
3.1.3 N′-2-isopropylphenyl-N-cyanoformamidine 4c
White solid; yield 87%; mp 125–126 °C; 1H NMR (DMSO-d6) 10.56 (bs, 1H, NH), 8.65, 8.58, (2s, 1H, CH), 7.48–7.10 (m, 4H, Ar), 3.21–3.05, (2ept, J1 = 6.9 Hz, J2 = 6.8 Hz, 1H, CH), 1.15 (d, J1 = 6.9 Hz, 6H, CH3); 13C NMR (DMSO-d6) 164.59, 161.12, 143.60, 141.15, 140.28, 130.88, 126.98, 126.46, 126.06, 125.66, 125.02, 124.77, 124.44, 124.12, 123.96, 121.54, 25.30, 24.77, 21.51, 21.13. Anal. calcd for C11H13N3: C, 70.56 H, 7.00 N, 22.44. Found: C, 70.65 H, 6.97 N, 22.38.
3.1.4 N′-4-isopropylphenyl-N-cyanoformamidine 4d
White solid; yield 90%; mp 90–91 °C; 1H NMR (DMSO-d6) 11.10 (bs, 1H, NH), 8.47, 9.03 (2s, 1H, CH), 7.23–7.58 (m, 4H, Ar), 2.78, 2.95 (m, 1H, CH), 1.181.16, (2d, J1 = 6.9 Hz, 3H, CH3); 13C NMR (DMSO-d6) 161.80, 158.94, 146.35, 133.59, 132.84, 127.46, 21.75, 21.80, 30.84, 31.00, 115.83, 119.11, 121.06, 124.70, 125.26, 125.50. Anal. calcd for C11H13N3: C, 70.56 H, 7.00 N, 22.44. Found: C, 70.61 H, 6.97 N, 22.42.
3.1.5 N′-2,4-dimethylphenyl-N-cyanoformamidine 4e
White solid; yield 97%; mp 138–139 °C; 1H NMR (DMSO-d6) 11.05 (bs, 1H, NH), 8.50, 8.95 (2s, 1H, CH), 6.87–7.35 (m, 3H, Ar), , 2.23, 2.21, 2.15 (3s, 6H, CH3); 13C NMR (DMSO-d6) 161.58, 158.68, 135.43, 133.50, 132.84, 131.41, 130.94, 128.25, 127.71, 119.90, 116.78, 116.50, 116.25, 113.21, 17.56, 17.53, 17.35, 16.90, 16.65. Anal. calcd for C10H11N3: C, 69.34 H, 6.40 N, 24.26. Found: C, 69.41 H, 6.37 N, 24.22.
3.1.6 N′-3,4-dimethylphenyl-N-cyanoformamidine 4f
White solid; yield 97%; mp 170–172 °C; 1H NMR (DMSO-d6) 11.02 (bs, 1H, NH), 9.01–8.44, (2s, 1H, CH), 7.42–6.96 (m, 3H, Ar), 2.21, 2.19, 2.17 (3s, 6H, CH3); 13C NMR (DMSO-d6) 161.61, 158.72, 135.45, 133.53, 132.89, 131.43, 130.92, 128.26, 127.75, 119.96, 116.82, 116.52, 116.25, 113.18, 17.58, 17.51, 17.41, 16.92, 16.73. Anal. calcd for C10H11N3: C, 69.34 H, 6.40 N, 24.26. Found: C, 69.40 H, 6.37 N, 24.23.
3.1.7 N′-2-methoxyphenyl-N-cyanoformamidine 4g
White solid; yield 96%; mp 125–126 °C, 1H NMR (DMSO-d6) 10.50 (bs, 1H, NH), 8.73, 8.39, (2s, 1H, CH), 8.00–6.86 (m, 4H, Ar), 3.86, 3.83, (2s, 3H, OCH3); 13C NMR (DMSO-d6) 163.69, 161.09, 159.68, 128.89, 127.58, 127.06, 126.54, 124.50, 123.37, 120.76, 119.06, 118.95, 118.85, 118.30, 110.28, 109.52, 53.98, 53.88. Anal. calcd for C9H9N3O: C, 61.70 H, 5.18 N, 23.99. Found: C, 61.79 H, 5.15 N, 23.95.
3.1.8 N′-3-methoxyphenyl-N-cyanoformamidine 4h
White solid; yield 93%; mp 167–168 °C; 1H NMR (DMSO-d6) 11.16 (bs, 1H, NH), 8.50, 9.14 (2s, 1H, CH), 7.35–6.68 (m, 4H, Ar), 3.78, 3.75 (2s, 3H, OCH3); 13C NMR (DMSO-d6) 163.58, 161.37, 160.25, 159.55, 139.07, 138.11, 130.28, 129.77, 117.75, 113.40, 110.84, 110.73, 110.22, 107.20, 103.60, 55.29, 55.20. Anal. calcd for C9H9N3O: C, 61.70 H, 5.18 N, 23.99. Found: C, 61.77 H, 5.16 N, 23.96.
3.1.9 N′-4-methoxyphenyl-N-cyanoformamidine 4i
White solid; yield 87%; mp 143–144 °C (lit.3 143–145 °C); 1H NMR (DMSO-d6) δH 10.86, 11.21(2bs, 1H, NH), 8.94, 8.43, (2s, 1H, CH), 7.60–6.90 (m, 4H, Ar), 3.79, 3.74, (2s, 3H, OCH3); 13C NMR (DMSO-d6) 163.59, 162.73, 160.45, 156.74, 156.61, 130.74, 129.92, 122.62, 119.42, 118.36, 114.64, 114.02, 55.25,55.20. Anal. calcd for C9H9N3O: C, 61.70 H, 5.18 N, 23.99. Found: C, 61.75 H, 5.17 N, 23.96.
3.1.10 N′-2,4-dimethoxyphenyl-N-cyanoformamidine 4j
White solid; yield 89%; mp 156–157 °C; 1H NMR (DMSO-d6) 10.60, 10.23, (2bd, J1 = 11.4 Hz, J2 = 4.7 Hz, 1H, NH), 8.56, 8.28 (2d, J1 = 11.4 Hz, J2 = 4.7 Hz, 1H, CH), 7.80–6.45 (m, 3H, Ar), 3.79, 3.76, 3.71 (3s, 6H, OCH3); 13C NMR (DMSO-d6) 161.50, 159.27, 154.11, 153.52, 142.96, 142.85, 126.28, 125.91, 117.66, 117.38, 112.47, 111.04, 110.74, 110.48, 107.93, 103.09, 56.39, 56.31, 55.85, 55.82. Anal. calcd for C10H11N3O2: C, 58.53 H, 5.40 N, 20.48. Found: C, 58.47 H, 5.38 N, 20.52.
3.1.11 N′-2,5-dimethoxyphenyl-N-cyanoformamidine 4k
White solid; yield 91%; mp 124–125 °C; 1H NMR (DMSO-d6) 10.54, 10.18 (2bd, J1 = 11.7 Hz, J2 = 4.7 Hz, 1H, NH), 8.50, 8.26 (2d, J1 = 11.7 Hz, J2 = 4.7 Hz, 1H, CH), 7.77–6.43 (m, 3H, Ar), 3.75, 3.70, 3.64 (3s, 6H, OCH3); 13C NMR (DMSO-d6) 161.50, 159.13, 154.15, 153.63, 142.90, 142.83, 126.31, 125.85, 117.62, 117.31, 112.42, 110.97, 110.71, 110.52, 107.96, 103.13, 56.34, 56.28, 55.80, 55.76. Anal. calcd for C10H11N3O2: C, 58.53 H, 5.40 N, 20.48. Found: C, 58.46 H, 5.37 N, 20.52.
3.1.12 N′-2-chlorophenyl-N-cyanoformamidine 4l
White solid; yield 76%; mp 156–157 °C; 1H NMR (DMSO-d6) 10.79 (bs, 1H, NH), 8.81, 8.59 (2s, 1H, CH), 7.82–7.18 (m, 4H, Ar); 13C NMR (DMSO-d6) 164.78, 161.15, 158.39, 132.95, 132.27, 130.99, 127.81, 127.47, 126.99, 126.14, 125.77, 125.66, 125.61, 123.51, 115.34, 113.84. Anal. calcd for C8H6ClN3: C, 53.50 H, 3.37 N, 23.40. Found: C, 53.57 H, 3.40 N, 23.34.
3.1.13 N′-3-chlorophenyl-N-cyanoformamidine 4m
White solid; yield 84%; mp 183–184 °C. 1H NMR (DMSO-d6) 11.28 (bs, 1H, NH), 9.16, 8.57 (2s, 1H, CH), 8.60–7.18 (m, 4H, Ar); 13C NMR (DMSO-d6) 162.61, 161.17, 159.88, 157.93, 137.46, 136.47, 131.90, 131.14, 129.08, 128.72, 123.06, 122.45, 118.56, 117.55, 115.36, 114.35. Anal. calcd for C8H6ClN3: C, 53.50 H, 3.37 N, 23.40. Found: C, 53.55 H, 3.40 N, 23.37.
3.1.14 N′-4-chlorophenyl-N-cyanoformamidine 4n
White solid; yield 81%; mp 191–192 °C (lit.[3] 191–193 °C); 1H NMR (DMSO-d6) 11.19 (bs, 1H, NH), 9.05, 8.49 (2s, 1H, CH), 7.65–7.23 (m, 4H, Ar); 13C NMR (DMSO-d6) 162.15, 159.54, 134.92, 133.97, 127.33, 127.23, 127.00, 126.89, 120.83, 117.61, 115.57. Anal. calcd for C8H6ClN3: C, 53.50 H, 3.37 N, 23.40. Found: C, 53.56 H, 3.41 N, 23.34.
3.1.15 N′-2,3-dichlorophenyl-N-cyanoformamidine 4o
White solid; yield 75%; mp 156–158 °C; 1H NMR (DMSO-d6) 10.97 (bs, 1H, NH), 8.78, 8.60 (2s, 1H, CH), 8.10–6.80 (m, 3H, Ar); 13C NMR (DMSO-d6) 161.09, 158.58, 142.56, 137.48, 134.22, 139.92, 129.69, 126.70, 126.26, 123.79, 120.16, 119.67, 116.64, 114.38, 113.13, 118.20. Anal. calcd for C8H5Cl2N3: C, 44.89 H, 2.35 N, 19.63. Found: C, 44.95 H, 2.32 N, 19.58.
3.1.16 N′-2,4-dichlorophenyl-N-cyanoformamidine 4p
White solid; yield 88%; mp 194–195 °C; 1H NMR (DMSO-d6) 10.83 (bs, 1H, NH), 8.79, 8.59 (2s, 1H, CH), 7.86–7.45 (m, 3H, Ar); 13C NMR (DMSO-d6) 166.15, 163.06, 134.37, 132.27, 131.29, 129.47, 129.24, 128.26, 128.09, 127.84, 127.55, 125.20, 117.20. Anal. calcd for C8H5Cl2N3: C, 44.89 H, 2.35 N, 19.63. Found: C, 44.93 H, 2.31 N, 19.59.
3.1.17 N′-2,5-dichlorophenyl-N-cyanoformamidine 4q
White solid; yield 77%; mp 161–162 °C; 1H NMR (DMSO-d6) 10.86 (bs, 1H, NH), 8.88, 8.61 (2s, 1H, CH), 8.07–7.30 (m, 3H, Ar); 13C NMR (DMSO-d6) 162.61, 160.43, 131.26, 131.21, 130.91, 130.68, 130.33, 129.74, 127.16, 125.14, 124.41, 121.42, 121.18, 120.60, 115.62, 113.82. Anal. calcd for C8H5Cl2N3: C, 44.89 H, 2.35 N, 19.63. Found: C, 44.96 H, 2.31 N, 19.58.
3.1.18 N′-2-bromophenyl-N-cyanoformamidine 4r
White solid; yield 71%; mp 136–137 °C; 1H NMR (DMSO-d6) 10.98, 10.65 (2bd, J1 = 11.7 Hz, J2 = 4.4 Hz, 1H, NH), 8.70, 8.56 (2d, J1 = 11.7 Hz, J2 = 4.4 Hz, 1H, CH), 7.70–7.10 (m, 4H, Ar); δC 164.88, 161.17, 136.36, 134.32, 132.41, 131.26, 130.99, 126.93, 126.87, 126.69, 126.33, 125.37, 124.53, 122.84, 116.12, 115.82. Anal. calcd for C8H6BrN3: C, 42.88 H, 2.70 N, 18.75. Found: C, 42.82 H, 2.68 N, 18.79.
3.1.19 N′-3-bromophenyl-N-cyanoformamidine 4s
White solid; yield 77%; mp 174–175 °C; 1H NMR (DMSO-d6) 11.34 (bs, 1H, NH), 9.16, 8.57 (2s, 1H, CH), 8.15–7.10 (m, 4H, Ar); 13C NMR (DMSO-d6) 161.14, 159.41, 140.67, 133.45, 129.57, 129.41, 128.87, 127.61, 124.20, 123.55, 123.10, 120.22, 119.89, 119.65, 118.06, 114.60. Anal. calcd for C8H6BrN3: C, 42.88 H, 2.70 N, 18.75. Found: C, 42.81 H, 2.66 N, 18.81.
3.1.20 N′-4-bromophenyl-N-cyanoformamidine 4t
White solid; yield 79%; mp 196–198 °C (lit.3 202–204 °C); 1H NMR (DMSO-d6) 11.43, 11.38, (2bd, J1 = 5.0 Hz, J2 = 12.2 Hz, 1H, NH), 9.07, 8.46, (2d, J1 = 5.0 Hz, J2 = 12.2 Hz, 1H, CH), 7.62–7.20 (m, 4H, Ar); 13C NMR (DMSO-d6) 162.28, 159.40, 114.83, 135.34, 134.51, 130.40, 130.21, 129.80, 120.94, 117.71, 115.71, 115.21. Anal. calcd for C8H6BrN3: C, 42.88 H, 2.70 N, 18.75. Found: C, 42.83 H, 2.67 N, 18.78.
3.2 Synthesis of N′-(2,4-dimethylphenyl)-N-methylformamidine 6
Methylamine hydrochloride (1.16 g, 17.4 mmol) was solubilized with 6 mL of water and added to a solution of 0.53 g (3.0 mmol) of N′-(2,4-dimethylphenyl)-N-cyanoformamidine in 3 mL of tetrahydrofuran. The pH was adjusted to about 10 by the addition of a sodium hydroxide solution and the mixture left to react for two hours, and then extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated to dryness to provide a crude product usable for the next step without the further purification (0.46 g, yield 98%).
1H NMR (CDCl3) 7.47 (s, H, NH), 6.96 (s, H, NCHN), 6.89–6.65 (m, 3H, Ar), 2.96 (s, 3H, CH3N), 2.27 (s, 3H, CH3), 2.22 (s, 3H, CH3).
3.3 Synthesis of D9-1,5-di-(2,4-dimethylphenyl)-3-methyl-1,3,5-triazapenta-1,4-diene (d9-Amitraz) 7
A mixture of d9-1-isocyano-2,4-dimethylbenzene (0.56 g, 4.00 mmol), N′-(2,4-dimethylphenyl)-N-methylformamidine (6) (0.91 g, 5.6 mmol) and copper (I) oxide (0.005 g, 0.08 mmol) was stirred in toluene at reflux temperature for two hours. After completion the reaction mixture was cooled, hydrolyzed with 5 mL of a saturated solution of ammonium chloride and extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated to dryness to provide a crude product that, purified by crystallization from cyclohexane, furnished 1.0 g of pure product (white solid; yield 84%; Mp 85–86 °C).
1H NMR (CDCl3) 6.94–6.70 (m, 3H, Ar), 3.49 (s, 3H, CH3N), 2.30 (s, 3H, CH3), 2.26 (s, 3H, CH3); 13C NMR (CDCl3) 161.35, 160.51, 145.22, 144,15, 129.04, 128.77 (t CD), 127.50, (t, CD), 125.01 (t, CD), 116.21, 120.33, 115.45, 113.92, 26.38, 21.51–19.30 (m, CD3), 18.92, 18.52–16.89 (m, CD3), 17.15.
4 Conclusion
We have developed a suitable and general one-pot synthesis of N′-aryl-N-cyanoformamidines (4) from primary aromatic amines, triethylorthoformate and cyanoamide via double nucleophilic substitution at the formyl carbon. This synthesis allows, in a one-step procedure, the introduction of a N-cyanoimino group that makes the formamidine carbon more electrophilic by electron-withdrawing effect, allowing a double and nucleophilic substitution on the orthoformate as for example in the preparation of unsymmetrical formamidine. This method with respect to those reported in the literature (Cereda et al., 1986; Schaefer and Gewald, 1976), allows its application to a considerable amount of substrates providing products in great yields and high purity without complicated purification processes but only by recrystallization. In fact it is important to note that no column chromatographic separation is needed. In addition, applying this procedure, we have synthesized labelled Amitraz like example of formamidine pesticides.
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