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Synthesis of novel N-heteroarylphenyl trifluoroacetamide derivatives under thermal and microwave conditions
∗Address: Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah, Saudi Arabia. Tel.: +966 545917568. rabiemohamed@hotmail.com (Mohamed R. Shaaban)
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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
An efficient routes to various kinds of heterocycles and fused heterocycles incorporated trifluoroacetamide moiety have been synthesized by the reaction of versatile N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide with thioamides and heterocyclic amines thermally and under microwave irradiation.
Keywords
Trifluoroacetylation
Trifluoroacetamides
α-Bromination
Heterocycles
Microwaves
1 Introduction
There has been a huge interest in the synthesis of fluorinated molecules which have wide applications in the field of pharmaceuticals and agrochemicals in recent years (Smart, 2001; Welch and Eswarakrishnan, 1991; Ojima et al., 1996). Recently, several examples in the literature show that molecules useful as pharmaceuticals and agrochemicals have both fluorine and heterocyclic rings incorporated in their framework. However, even with the additions of new fluorinating agents that have been developed over the past decades, the selective introduction of fluorine into some molecules is far from easy, especially on the large scale necessary for the production of pharmaceuticals. Also, the advantage of having heterocycles in drug molecules is well known and many commercialized drugs now have been developed which contain several heterocycles pendant to fluorinated groups (Kukhar and Soloshonok, 1995; Hiyama, 2000; Becker, 1996). This group of compounds now gives the drug designer the ability to integrate the roles of both fluorine and heterocycles into the pharmaceutical structure in a single step. In this context, the introduction of the trifluoroacetamido group into organic molecules is a topic of growing interest in organofluorine chemistry. Efficient introduction of this group into bioactive molecules, especially in the positions responsible for their physiological profile, becomes a very important direction in pharmaceutical studies that stimulates work directed to elaborate the synthetic methodologies for various compounds containing this group (McClinton and McClinton, 1992; Tiejun et al., 1999; Khalaf et al., 2012). 2,2,2-Trifluoroacetamide is a useful intermediate for the synthesis of fluorinated molecules. It has been used to prepare molecules which function as receptor agonists for treatment of metabolic disorders related to insulin resistance or hyperglycemia (Rasmussen et al., 2000), antiviral and antitumor (Stephens et al., 2001; Nishimura et al., 1994). Other substituted trifluoroacetamides have been employed as intermediates in the synthesis of medicinally useful compounds that function as antimicrobial agents (Bekhit et al., 2006). These compounds exhibit anti inflammatory and immunomodulatory activities (Vigorita et al., 1990). Because of this widespread use, several reagents and methods for the trifluoroacetylation of amines have been developed. Reagents for trifluoroacetamidation that have been developed include, for example, trifluoroacetic anhydride, S-ethyltrifluorothioacetate, N-(trifluoroacetyl)imidazole, 2-(trifluoroacetyl)oxy]pyridine, trifluoroacetyltriflate, N-(trifluoroacetoxy)succinimide, (trifluoroacetyl)benzotriazole, and N-(trifluoroacetyl)succinimide. Very recently, trifluoroacetylation of arylamines using trifluoroacetic acid (TFA) and poly-phosphoric acid trimethylsilylester was reported (Salazar et al., 2003). For several reasons, it is evident that the use of TFA alone would be both economically and environmentally advantageous. On the other hand, microwave irradiation has recently demonstrated its utility as an energy source to improve yields and/or save reaction conditions, especially in the field of heterocyclic synthesis (Kappe and Stadler, 2005; Kappe, 2008; Dallinger and Kappe, 2007). The use of the pressurized microwave irradiation can be very advantageous to many chemistries where the solvent can be heated up to temperatures that are 2–4 times their respective boiling points and thus providing a large rate enhancement. In addition, keeping the atmosphere from moisture that may affect the moisture sensitive reagents decreases the possibility of formation of the undesired byproducts. In continuation of our interest in the synthesis of fluorinated organic compounds (Elwahy and Shaaban, 2010; Shaaban et al., 2009 and Shaaban, 2008; Iwayasu et al., 2002; Shaaban and Fuchigami, 2002; Shaaban et al., 2001, 2000a,b), we report here a convenient, and environmentally friendly synthesis of novel N-phenyltrifluoroacetamide derivatives pendant to several heterocyclic moiety under microwaves irradiation.
2 Experimental section
2.1 Materials and methods
All melting points were measured on a Gallenkamp melting point apparatus. The infrared spectra were recorded in potassium bromide disks on a Pye Unicam SP 3–300 and Shimadzu FT IR 8101 PC infrared spectrophotometers. The NMR spectra were recorded on a Varian Mercury VXR-300 NMR spectrometer (1H NMR (300 MHz) and 13C NMR (75.46 MHz)) and a Bruker-500 NMR spectrometer (1H NMR (500 MHz) and 13C NMR (125.77 MHz)) were run in deuterated chloroform (CDCl3) or dimethyl sulfoxide (DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer at 70 eV. Elemental analyses were carried out at the Micro-analytical Centre of Cairo University, Giza, Egypt and recorded on a Elementar-Vario EL automatic analyzer. Microwave irradiation was performed using the MARS system of CEM which is a multi-mode platform equipped with a magnetic stirring plate and a rotor that allows the parallel processing of several vessels per batch. We used the HP-500 (Teflon (TFA) insert) (vessel volume 80 mL, max pressure 350 psi, max temperature 210 °C) in order to get the maximum save operation.
2.2 Synthesis of N-(4-acetylphenyl)-2,2,2-trifluoroacetamide (2)
A mixture of p-aminoacetophenone (1) (3 mmole), TFA (6 mmole), and p-xylene (10 mL) was heated under reflux (In an oil bath) for 5 h. Then solvent was evaporated in vacuum. The residue was chromatographed on a silica gel column and eluted with AcOEt/n-hexane (1:4) to afford N-(4-acetylphenyl)-2,2,2-trifluoroacetamide (2) in 95%. The physical and spectral data of the synthesized compound are listed below.
Colorless crystals, mp 155 °C; IR (KBr) vmax/cm−1: 3302 (NH), 1748, 1671 (2 C⚌O); 1H NMR (CDCl3): δ 2.64 (s, 3H), 7.75 (d, 2H, J = 10 Hz), 8.02 (d, 2H, J = 10 Hz), 11.82 (s, 1H); 13C NMR (CDCl3): 26.5, 112.0, 114.7, 116.6, 129.8, 134.6, 139.4, 155.1(q), 198.0. MS (m/z): 231.00 (M+). Anal. Calcd. for C10H8F3NO2 (231.05): C, 51.96; H, 3.49; N, 6.06. Found: C, 51.94; H, 3.46; N, 6.08%.
2.3 Synthesis of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3)
2.3.1 Thermal method
To a stirred solution of N-(4-acetylphenyl)-2,2,2-trifluoroacetamide (2) (l0 mmole) and p-toluenesulfonic acid (p-TsOH) (5.6 g, 20 mmole) in acetonitrile (50 mL) was slowly added N-bromosuccinimide (NBS) (1.78 g, 10 mmole). After addition of NBS was complete, the reaction mixture was refluxed with stirring for 2 h then left to cool to room temperature. The solvent was evaporated in vacuum and the residue was dissolved in chloroform (50 mL), washed with water (2 × 20 mL) and dried over MgSO4. After evaporation of the solvent the resulting solid was recrystallized from benzene to afford the corresponding α-bromo ketone 3.
2.3.2 Microwave method (MW)
To a solution of N-(4-acetylphenyl)-2,2,2-trifluoroacetamide (2) (10 mmole) in dry acetonitrile (50 mL) were added p-toluenesulfonic acid (p-TsOH) (5.6 g, 20 mmole), and N-bromosuccinimide (NBS) (1.78 g, 10 mmole) and the mixture was mixed in a HP-500 Plus process vessel. The vessel was capped properly and irradiated by microwaves under pressurized conditions (17.2 bar, 100 °C) for 20 min. The solvent was evaporated in vacuum and the residue was dissolved in chloroform (50 mL), washed with water (2 × 20 mL) and dried over MgSO4. After evaporation of the solvent the resulting solid was recrystallized from benzene to afford N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3). The physical and spectral data of the synthesized compound are listed below.
White crystals, mp 165 °C; IR (KBr) vmax/cm−1: 3305 (NH), 1736, 1697 (2 C⚌O); 1H NMR (CDCl3): δ 4.78 (s, 2H), 7.94 (d, 2H, J = 10 Hz), 8.08 (d, 2H, J = 10 Hz), 11.62 (s, 1H). MS (m/z): 311(M++2), 309 (M+). Anal. Calcd. for C10H7BrF3NO2: C, 38.74; H, 2.28; N, 25.77. Found: C, 38.72; H, 2.25; N, 25.77%.
2.4 Reactions with thioamides: synthesis of N-(4-(thiazol-4-yl)phenyl)-2,2,2-trifluoroacetamide derivatives (5a-d)
2.4.1 Thermal method
A mixture of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) (5 mmole), thiourea (4a), N-methylthiourea (4b), N-phenylthiourea(4c) or thioacetamide (4d) (10 mmole) in absolute ethanol was heated at refluxing temperature for 1 h. The reaction mixture was then cooled and the resulting precipitate was collected by filtration, washed thoroughly with water and dried. Recrystallization from ethanol afforded the corresponding thiazole derivatives 5a-d.
2.4.2 Microwave method (MW)
2.4.2.1 General procedure
To a solution of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) (10 mmole) in isopropyl alcohol (50 mL) were added thioamide derivatives 4a-d (20 mmole) and the mixture was mixed in a HP-500 Plus process vessel. The vessel was capped properly and irradiated by microwaves under pressurized conditions (17.2 bar, 150 °C) for 15 min. The solvent was evaporated in vacuum and the residue was washed with water and dried then recrystallized from alcohol to afford N-(4-(2-aminothiazol-4-yl)phenyl)-2,2,2-trifluoroacetamide derivatives 5a-d in moderate to good yields. The physical and spectral data of the synthesized compounds are listed below.
2.4.2.2 N-(4-(2-Aminothiazol-4-yl)phenyl)-2,2,2-trifluoroacetamide (5a)
White crystals, mp 270 °C; IR (KBr) vmax/cm−1: 3389, 3281, 3120 (NH2, NH), 1711 (C⚌O), 1626 (C⚌N); 1H NMR (CDCl3): δ 3.64 (br, 2H), 7.24 (s, 1H), 7.80 (d, 2H, J = 10 Hz), 8.02 (d, 2H, J = 10 Hz), 11.47 (s, 1H); 13C NMR (CDCl3): 102.7, 114.5, 116.8, 119.0, 121.0, 126.1, 136.9, 154.5(q), 170.1. MS (m/z): 287 (M+). Anal. Calcd. for C11H8F3N3OS: C, 45.99; H, 2.81; N, 14.63. Found: C, 46.01; H, 2.83; N, 14.61%.
2.4.2.3 2,2,2-Trifluoro-N-(4-(2-(methylamino)thiazol-4-yl)phenyl)acetamide (5b)
White crystals, mp 267 °C; IR (KBr) vmax/cm−1: 3364, 3242 (2 NH), 1718 (C⚌O), 1617 (C⚌N); 1H NMR (CDCl3): δ 2.64 (s, 3H), 3.23 (br, H), 7.04 (s, 1H), 7.75 (d, 2H, J = 10 Hz), 8.02 (d, 2H, J = 10 Hz), 11.65 (s, 1H). MS (m/z): 301.0 (M+). Anal. Calcd. for C12H10F3N3OS: C, 47.48; H, 3.35; N, 13.95. Found: C, 47.46; H, 3.32; N, 13.97%.
2.4.2.4 2,2,2-Trifluoro-N-(4-(2-(phenylamino)thiazol-4-yl)phenyl)acetamide (5c)
White crystals, mp 279 °C; IR (KBr) vmax/cm−1: 3422, 3235 (2 NH), 1714 (C⚌O), 1608 (C⚌N); 1H NMR (CDCl3): δ 3.23 (br, 1H), 7.06 (s, 1H), 7.75 (d, 2H, J = 10 Hz), 7.08–7.15 (m, 5H), 8.02 (d, 2H, J = 10 Hz), 11.65 (s, 1H); 13C NMR (CDCl3): 90.0, 102.9, 114.5, 116.9, 126.2, 129.0, 131.7, 136.1, 141.1, 149.2, 154.5(q), 161.8, 163.2. MS (m/z): 363 (M+). Anal. Calcd. for C17H12F3N3OS: C, 56.19; H, 3.33; N, 11.65. Found: C, 56.21; H, 3.30; N, 11.62%.
2.4.2.5 2,2,2-Trifluoro-N-(4-(2-methylthiazol-4-yl)phenyl)acetamide (5d)
White crystals, mp 258 °C; IR (KBr) vmax/cm−1: 3153 (NH), 1709 (C⚌O), 1652 (C⚌N); 1H NMR (CDCl3): δ 2.74 (s, 3H), 5.54 (s, 1H), 7.76 (d, 2H, J = 10 Hz), 7.96 (d, 2H, J = 10 Hz), 11.37 (s, 1H); 13C NMR (CDCl3): 18.7, 113.8, 116.8, 121.0, 126.5, 131.1, 135.9, 152.6, 154.5(q), 166.0. MS (m/z): 286 (M+). Anal. Calcd. for C12H9F3N2OS: C, 50.35; H, 3.17; N, 9.79. Found: C, 50.37; H, 3.15; N, 9.81%.
2.5 Reactions with heterocyclic amines
2.5.1 Thermal method
2.5.1.1 General procedure
A mixture of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) (1 mmole) and the appropriate heterocyclic amine, 2-aminothiazole (6), 2-amino-5-(triflouoromethyl)1,3,4-thiadiazole (8), 2-aminobenzothiazole (10), 2-aminopyridine (12a), 2-aminopyrimidine (12b), 3-amino-1,2,4-triazole (19) (1 mmole), in absolute ethanol (15 mL) was refluxed for 4 h, then left to cool to room temperature. The precipitated product that formed was filtered off, washed with ethanol and dried. Recrystallization from the proper solvent afforded compounds 7, 9, 11, 16a, 16b and 20.
2.5.2 Microwave method (MW)
2.5.2.1 General procedure
An isopropyl alcohol solution of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) (1 mmole) and the appropriate heterocyclic amine (1 mmole) was mixed in a HP-500 Plus process vessel. The vessel was capped properly and irradiated with microwave under conditions (17.2 bar, 150 °C) for 25 min, the reaction mixture was evaporated in vacuum and the residual solid was taken in water, filtered off, and dried and finally recrystallized from dilute ethanol to afford the corresponding 7, 9, 11, 16a, 16b and 20. The physical and spectral data of synthesized compounds are listed below:
2.5.2.2 2,2,2-Trifluoro-N-(4-(imidazo[2,1-b]thiazol-6-yl)phenyl)acetamide (7)
White crystals, mp 300 °C; IR (KBr) vmax/cm−1: 3147 (NH), 1711 (C⚌O), 1602 (C⚌N); 1H NMR (CDCl3): δ 7.08 (d, 1H, J = 4.5 Hz), 7.36 (d, 1H, J = 4.5 Hz), 7.94 (d, 2H, J = 10 Hz), 8.09 (d, 2H, J = 10 Hz), 9.56 (s, 1H), 11.67 (s, 1H); 13C NMR (CDCl3): 54.8, 107.2, 114.3, 116.6, 120.6, 129.5, 130.6, 141.4, 154.7(q), 169.0, 189.2. MS (m/z): 311 (M+). Anal. Calcd. for C13H8F3N3OS: C, 50.16; H, 2.59; N, 13.50. Found: C, 50.15; H, 2.61; N, 13.53%.
2.5.2.3 2,2,2-Trifluoro-N-(4-(2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)phenyl)acetamide (9)
White crystals, mp 260 °C; IR (KBr) vmax/cm−1: 3341, (NH), 1727(C⚌O), 1697 (C⚌N); 1H NMR (CDCl3): δ 7.61 (d, 2H, J = 10 Hz), 7.98 (d, 2H, J = 10 Hz), 8.90 (s, 1H), 11.39 (s, 1H); 13C NMR (CDCl3): 111.2, 119.7, 121.2, 125.5, 130.4, 135.9, 144.5, 146.4, 149.0, 154.5(q), 156.2(q). MS (m/z): 380 (M+). Anal. Calcd. for C13H6F6N4OS: C, 41.06; H, 1.59; N, 14.73. Found: C, 41.09; H, 1.62; N, 14.75%.
2.5.2.4 2,2,2-Trifluoro-N-(4-(imidazo[2,1-b]benzthiazol-6-yl)phenyl)acetamide (11)
White crystals, mp 258 °C; IR (KBr) vmax/cm−1: 3341, 1715 (C⚌O), 1610 (C⚌N); 1H NMR (CDCl3): δ 7.42–7.45 (t, 1H, J = 8 Hz), 7.56–7.59 (t, 1H, J = 8.5 Hz), 7.56 (d, 1H, J = 10 Hz), 7.90 (d, 1H, J = 10 Hz), 7.98 (d, 2H, J = 7.5 Hz), 8.04 (d, 2H, J = 7.5 Hz), 8.78 (s, 1H), 11.33 (s, 1H); 13C NMR (CDCl3): 109.0, 113.2, 114.6, 116.9, 121.2, 125.0, 125.1, 126.6, 131.2, 131.7, 132.4, 145.6, 146.9, 154.1(q), 169.0. MS (m/z): 361 (M+). Anal. Calcd. for C17H10F3N3OS: C, 56.51; H, 2.79; N, 11.63. Found: C, 56.49; H, 2.78; N, 11.60%.
2.5.2.5 2,2,2-Trifluoro-N-(4-(imidazo[1,2-a]pyridin-3-yl)phenyl)acetamide (16a)
White crystals, mp 298 °C; IR (KBr) vmax/cm−1: 3294 (NH), 1717 (C⚌O), 1656 (C⚌N); 1H NMR (CDCl3): δ 7.51 (t, 1H, J = 8.5 Hz), 7.53 (d, 1H, J = 10 Hz), 7.91 (d, 2H, J = 10 Hz), 7.96 (t, 1H, J = 8.5 Hz), 7.98 (d, 2H, J = 10 Hz), 8.86, (s, 1H), 8.93 (d, 1H, J = 10 Hz), 11.56 (s, 1H); 13C NMR (CDCl3): 111.1, 112.0, 114.4, 116.7, 119.0, 121.5, 126.9, 129.0, 133.4, 134.7, 137.9, 140.1, 154.8(q). MS (m/z): 305 (M+). Anal. Calcd. for C15H10F3N3O: C, 59.02; H, 3.30; N, 13.77. Found: C, 59.00; H, 3.31; N, 13.76%.
2.5.2.6 2,2,2-Trifluoro-N-(4-(imidazo[1,2-a]pyrimidin-3-yl)phenyl)acetamide (16b)
White crystals, mp 300 °C; IR (KBr) vmax/cm−1: 3426 (NH), 1719 (C⚌O), 1662 (C⚌N); 1H NMR (CDCl3): δ 7.52 (t, 1H, J = 8.5 Hz), 7.91 (d, 2H, J = 10 Hz), 7.95 (d, 1H, J = 10 Hz), 8.02 (d, 2H, J = 10 Hz), 8.84, (s, 1H), 8.93 (d, 1H, J = 10 Hz), 11.55 (s,1H); 13C NMR (CDCl3): 111.1, 112.0, 114.4, 116.7, 117.2, 121.5, 123.5, 126.9, 133.3, 138.0, 140.1, 154.5(q). MS (m/z): 306 (M+). Anal. Calcd. for C14H9F3N4O: C, 54.91; H, 2.96; N, 18.29. Found: C, 54.94; H, 2.93; N, 18.32%.
2.6 Synthesis of 2,2,2-Trifluoro-N-(4-(imidazo[1,2-a]pyridine-3-carbonyl)phenyl)acetamide (15)
A mixture of 2-aminopyridine (12a) (5 mmole), in dry benzene, dimethylformamide dimethylacetal (13) (DMF-DMA) (15 mmole) was heated at refluxing temperature for 8 h. The solvent was then removed in vacuum and the remaining oil was dried, then added to N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) (5 mmole), in absolute EtOH. The mixture was heated at refluxing temperature for 2 h or under microwave irradiation for 5 min at 80 °C using same experimental protocol in above reactions. The reaction mixture was then allowed to cool and the resulting solid was collected by filtration, washed thoroughly with ethanol and dried. Recrystallization from EtOH afforded the corresponding carbonyl analog of the fused heterocyclic derivative 15.
White crystals, mp 250 °C; IR (KBr) vmax/cm−1: 3295 (NH), 1718 (C⚌O), 1677 (C⚌O); 1H NMR (CDCl3): δ 7.35 (t, 1H, J = 8.5 Hz), 7.67 (t, 1H, J = 8.5 Hz), 7.88–7.98 (m, 5H), 8.30 (s, 1H), 9.63 (d, 1H, J = 10 Hz), 11.55 (s, 1H); MS (m/z): 333 (M+). Anal. Calcd. for C16H10F3N3O2: C, 57.66; H, 3.02; N, 12.61. Found: C, 57.36; H, 3.04; N, 12.81%.
2.7 Reaction with aminotriazolethiol derivatives
2.7.1 Thermal Method
2.7.1.1 General procedure
A mixture of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) (5 mmole), aminotriazolethiol derivatives 17a,b (5 mmole) in absolute ethanol was heated at refluxing temperature for 2 h. The reaction mixture was then cooled and the resulting precipitate was collected by filtration, washed thoroughly with ethanol and dried. Recrystallization from ethanol afforded the corresponding fused heterocyclic derivatives 18a and 18b.
2.7.2 Microwave method (MW)
2.7.2.1 General procedure
An isopropyl alcohol solution of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) (1 mmole) and the appropriate aminotriazolethiol derivatives 17a,b (1 mmole) was mixed in a HP-500 Plus process vessel. The vessel was capped properly and irradiated with microwave under conditions (17.2 bar, 150 °C) for 15 min, the reaction mixture was evaporated in vacuum and the residual solid was taken in water, filtered off, and dried and finally recrystallized from ethanol to afford the corresponding 18a and 18b. The physical and spectral data of the 18a,b are listed below:
2.7.2.2 2,2,2-Trifluoro-N-(4-(3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)phenyl)acetamide (18a)
White crystals, mp 270 °C; IR (KBr) vmax/cm−1: 3253 (NH), 1724 (C⚌O), 1610 (C⚌N); 1H NMR (CDCl3): δ 2.52 (s, 3H), 4.38 (s, 2H), 7.89 (d, 2H, J = 8.5 Hz), 8.09 (d, 2H J = 8.5 Hz), 11.57 (s, 1H); 13C NMR (CDCl3): 9.8, 22.6, 114.4, 116.7, 120.9, 128.3, 130.2, 139.4, 150.4, 153.7, 154.5(q). MS (m/z): 341 (M+). Anal. Calcd. for C13H10F3N5OS: C, 45.75; H, 2.95; N, 20.52. Found: C, 45.72; H, 2.93; N, 20.55%.
2.7.2.3 2,2,2-Trifluoro-N-(4-(3-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)phenyl)acetamide (18b)
White crystals, mp 269 °C; IR (KBr) vmax/cm−1: 3165 (NH), 1717 (C⚌O), 1605 (C⚌N); 1H NMR (CDCl3): δ 4.46 (s, 2H), 7.57–7.62 (m, 3H), 7.89–7.91 (m, 2H), 8.02 (d, 2H, J = 10 Hz), 8.08 (d, 2H, J = 10 Hz), 11.60 (s, 1H); 13C NMR (CDCl3): 22.5, 114.4, 116.7, 120.9, 125.9, 127.9, 128.7, 130.1, 139.4, 142.5, 150.4, 151.5, 154.5(q), 155.1. MS (m/z): 403 (M+). Anal. Calcd. for C18H12F3N5OS: C, 53.60; H, 3.00; N, 17.36. Found: C, 53.58; H, 3.02; N, 17.32%.
2.7.2.4 N-(4-(7H-Imidazo[2,1-c][1,2,4]triazol-5-yl)phenyl)-2,2,2-trifluoroacetamide (20)
White crystals, mp 282 °C; IR (KBr) vmax/cm−1: 3341, 1714 (C⚌O), 1610 (C⚌N); 1H NMR (CDCl3): δ 5.94 (s, 1H), 7.96 (d, 2H, J = 10 Hz), 8.14 (d, 2H, J = 10 Hz), 8.51 (s, 1H), 8.76 (s, 1H), 11.69 (s, 1H); 13C NMR (CDCl3): 51.3, 54.8, 114.3, 116.6, 120.6, 130.4, 141.6, 150.7, 154.7(q), 189.4. MS (m/z): 295 (M+). Anal. Calcd. for C12H8F3N5O: C, 48.82; H, 2.73; N, 23.72. Found: C, 48.80; H, 2.75; N, 23.75%.
3 Results and discussion
N-(4-acetylphenyl)-2,2,2-trifluoroacetamide (2) is a versatile fluorinated building block, its synthesis even under conventional methods is quite unclear since most of the methods reported are patents and/or with no details. N-(4-acetylphenyl)-2,2,2-trifluoroacetamide (2) was readily obtained by refluxing p-aminoacetophenone (1) with excess amount of TFA in p-xylene (Scheme 1). The structure of the trifluoroacetamide derivative 2 was confirmed by its elemental analyses and spectral data. The 1H NMR spectrum of 2, displayed a singlet signal at δ 2.64 due to the acetyl group protons, two doublets at δ 7.75 and 8.02 (J = 10 Hz) due to aromatic ring protons and a singlet at δ 11.82 due to NH proton. The presence of the trifluoromethyl group was confirmed by recording the 13C NMR spectra, where the appearance of the quartet signal at δ 155 (JC-F = 375 Hz) for the carbon of the CF3 group was observed. The IR spectrum exhibited a characteristic absorption band at 3302 cm−1 due to NH function and revealed the presence of absorption band corresponding to carbonyl groups at 1748 and 1671 cm−1. The mass spectrum showed the molecular ion peak at (m/z): 231.
Synthesis of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3).
Next, the bromination of N-(4-acetylphenyl)-2,2,2-trifluoroacetamide (2) has been investigated. N-bromosuccinimide (NBS) has been classically utilized for the α-bromination of ketones via radical process promoted by radical initiators such as AIBN and benzoyl peroxide in CCl4 (Diwu et al., 1998; Aoyama et al., 2004; De Kimpe and Verhé, 1988). In this work, the reaction of N-(4-acetylphenyl)-2,2,2-trifluoroacetamide (2) with NBS in the presence of p-toluenesulfonic acid (p-TsOH) in acetonitrile afforded the corresponding α-bromoketone, N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) as a single monobrominated product under microwave irradiation as well as conventional conditions as shown in Scheme 1. In general the microwave conditions afforded a high yield compared with the conventional heating.
It has been noticed continuously over the years that thiazoles possess some interesting biological activities (Ergenc et al., 1999; Carter et al., 1999; Badorc et al., 1997; Rudolph et al., 2001). Thus, treatment of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) with thioureas 4a,b and thioacetamide 4c under microwave conditions in isopropyl alcohol or conventionally in absolute ethanol afforded products identified as N-(4-(2-thiazol-4-yl)phenyl)-2,2,2-trifluoroacetamide derivatives 5a-c as outlined in Scheme 2. It should be noted that the yield of reaction products under microwave irradiation was higher than that of conventional heating as shown in Table 1 (See Table 2).
Synthesis of N-(4-(2-thiazol-4-yl)phenyl)-2,2,2-trifluoroacetamide derivatives 5a-d.
5a-d
R
Yield%
MW yield%
5a
NH2
65
75
5b
NH-CH3
62
87
5c
NH-Ph
53
74
5d
Me
82
93
Product
Yield%
MW yield%
7
57
66
9
42
57
11
63
76
The structures of compounds 5a-c were established on the basis of their elemental and spectral analyses. The 1H NMR spectrum of 5d, taken as a typical example, displayed singlet signal due to the methyl group protons in the range of δ 2.74 ppm. Also, displayed signals in the range of δ 7.76–7.97 ppm due to aromatic protons, in addition to a singlet signal at δ 5.54 ppm due to CH of thiazole proton, and a singlet at δ 11.37 ppm due to NH proton.
In all products the presence of the trifluoromethyl group was confirmed by recording the 13C NMR spectra, where the appearance of the quartet signal due to the direct C-F coupling at δ 154 for the carbon of the CF3 group was observed.
A lot of work on the synthesis and biological activities of the condensed imidazo[2,1-b]thiazoles has been reported since the discovery of novel broad spectrum anthelmintic, tetramisole (Thienopont et al., 1966). Imidazothiazole derivatives have been shown to display potent antitumor and fungistatic activities (Andreani et al., 2005a,b; Robert et al., 1990; Andreani et al., 1999). In this context, N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) undergoes cyclocondensation upon treatment with 2-aminothiazole (6), in ethanol or isopropyl alcohol, under thermal conditions and microwave irradiation to afford the corresponding imidazo[2,1-b]thiazole derivative 7, (Scheme 3).
Synthesis of fused thiazoles, benzthiazoles and thiadiazoles.
Also, N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) undergoes cyclocondensation upon treatment with 2-aminobenzothiazole (10), in ethanol or isopropyl alcohol, under thermal conditions and microwave irradiation to afford the corresponding 2,2,2-trifluoro-N-(4-(imidazo[2,1-b]benzthiazol-6-yl)phenyl)acetamide derivative (11) as outlined in (Scheme 3). Recently, imidazolo[2,1-b]benzothiazole derivatives, were found to act as potential p53 inhibitors (Michael et al., 2011) and have antimicrobial activity (Trapani et al., 2001).
In a similar manner the cyclocondensation reactions of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) with 2-amino-5-trifluoromethy1,3,4-thiazdiazole (8) under thermal conditions as well as microwave irradiation in isopropyl alcohol afforded the corresponding 2,2,2-trifluoro-N-(4-(2-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)phenyl)acetamide (9) (Scheme 3).
Proposed mechanism for the synthesis of fused imidazo heterocycles 7, 9 and 11 is depicted in Scheme 4. The first step is the formation of an acyclic intermediate by the nucleophilic attack of nitrogen of azole ring on the bromine-carrying carbon of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) resulting in the formation of the N–C bond with simultaneous transfer of amino lone pair of electrons toward C-2 of the azole ring accompanied by the elimination of HBr molecule. In the next step, an attack by the lone pair of electrons from imino nitrogen atom at the carbonyl carbon yields a cyclic intermediate which looses a water molecule leading to the formation of fused imidazoderivatives 7, 9 or 11.
Mechanism of synthesis of fused thiazoles, benzthiazoles and thiadiazoles.
In the past few decades, imidazo[1,2-a]pyridines and the related imidazo[1,2-a]pyrimidines have received significant attention from the pharmaceutical industry owing to their interesting biological activities displayed over a broad range of therapeutic classes (Katritzky et al., 2003). While there are a number of synthetic routes to the imidazo[1,2-a]pyridine ring system, the most common approach involves the treatment of 2-aminopyridines with α-halocarbonyl compounds. However, this approach does not readily lend itself to a diversity oriented synthesis under conventional conditions. In this work, N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) was allowed to react with some 2-aminopyridine 12a and 2-aminopyrimidine 12b under thermal as well as microwave conditions which led to the formation of the targeted imidazopyridines 16a and imidazopyrimidines 16b, respectively as shown in (Scheme 5).![Synthesis of imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidines derivatives.](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2013.11.003-fig5.png)
Synthesis of imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidines derivatives.
The structure of the products 16a,b was confirmed by their spectral data as well as by their elemental analyses. The 1H NMR spectra of compounds 16a,b showed characteristic signals due to the pyridine and pyrimidine ring protons at the expected chemical shifts and integral values.
The carbonyl analog of the targeted imidazopyridine 15 could be synthesized by the reaction of N,N-dimethyl-N′-(pyridin-2-yl)formimidamide 14 with N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) under microwave irradiation or in refluxing ethanol (Scheme 5). Proposed mechanism for the synthesis of carbonyl analog of the targeted imidazopyridine 15 is depicted in Scheme 6.![Mechanism of the synthesis of imidazo[1,2-a]pyridine derivative 15.](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2013.11.003-fig6.png)
Mechanism of the synthesis of imidazo[1,2-a]pyridine derivative 15.
The IR spectrum of compound 15 (taken as an example) in KBr showed, in addition to the expected peaks of the imidazopyridines 16a, an extra peak at wave numbers near 1677 cm−1 corresponding to the C⚌O group. The presence of C⚌O band was an evidence for the pathway of the cyclocondensation of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) with the N,N-dimethyl-N′-(pyridin-2-yl)formimidamide 14 as shown in Scheme 5. Moreover, the 1H NMR spectra of the imidazopyridine 15 showed that the C5-H signal of 15 is a downfield of the corresponding proton for 16a, respectively which provide an additional support for the suggestion that the carbonyl group anisotropy impacts the position of the aforementioned 1H NMR signals (aromatic region) as shown in Fig. 1.
Aromatic region of the 1H NMR spectra of the 15 and 16a.
Attempts were made to obtain the 3-acylimidazo[1,2-a]pyrimidine 15 via the alternative one pot three component reaction of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3), 2-aminopyridine (12a), and dimethylformamide dimethylacetal (13) under solvent free conditions. The reaction afforded the non carbonyl analog imidazopyrimidines 16 as shown in Scheme 5.
The latter structure was established on the basis of elemental analysis and spectral data. For example, the 1H NMR spectrum of 16a, displayed triplet signals at δ 7.51, 7.96 ppm, and doublets at δ 7.53, 7.91, 7.98, and 8.93 ppm due to aromatic and pyridine ring protons. In addition, a singlet signal at δ 8.86 ppm due to the CH-imidazole proton and a singlet signal at 11.69 ppm due to the NH proton were present. The presence of the trifluoromethyl group was confirmed by the appearance of the quartet signal at δ 154 ppm for the carbon of the CF3 group in the 13C NMR spectra of the products.
The synthetic utility of N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) for novel s-triazolo[3,4-b]thiadiazines 18a,b is outlined in (Scheme 7). 4-Amino-3-mercapto-1,2,4-triazole derivatives 17a,b were chosen as ideal heterocyclic reagents. The amino and mercapto groups of these compounds serve as readily accessible nucleophilic centers for the preparation of N-bridged heterocycles. Thus, the reaction of 3 with 17a,b in isopropyl alcohol under microwave irradiation or in anhydrous ethanol under reflux afforded 18a,b in good yields as shown in (Scheme 7).![Synthesis of s-triazolo[3,4-b]thiadiazines and imidazo[2,1-c][1,2,4]triazole derivatives.](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2013.11.003-fig8.png)
Synthesis of s-triazolo[3,4-b]thiadiazines and imidazo[2,1-c][1,2,4]triazole derivatives.
The structures of the products 18a,b were established on the basis of their elemental analyses and spectral data.
Also, the reaction of 2-amino-1,2,4-triazole with N-(4-(2-bromoacetyl)phenyl)-2,2,2-trifluoroacetamide (3) was investigated. Thus a mixture of 19 and 3 was irradiated in isopropyl alcohol for 25 min under microwave or refluxed in ethanol till the TLC indicated the complete disappearance of the starting material. The reaction afforded the novel N-(4-(7H-imidazo[2,1-c][1,2,4]triazol-5-yl)phenyl)-2,2,2-trifluoroacetamide 20 in 62% yield under microwave conditions and 42% yield using conventional heating (Scheme 7). The structure of 20 was assigned on the basis of its IR, 1H NMR and 13C NMR spectral data and was confirmed on the basis its mass spectrum. The IR spectrum of 5a showed an absorption band at 3341 cm−1 which was assigned to the N–H stretching of the NH group. The functional group region of the spectrum also exhibited absorption bands at 1714 cm−1 (C⚌O stretching). 1H NMR of 20 displayed characteristic two singlets for two single protons at δ 8.51 and 8.76 ppm which were clearly assigned to imidazole ring proton and triazole proton, respectively. A singlet due to one proton resonating at δ 11.69 ppm was assigned to the NH group of NHCOCF3. In addition four aromatic protons of the phenyl ring were easily identified as two doublets at δ 7.94 and 8.13 ppm.
4 Conclusion
In conclusion, a facile synthesis of novel series of 2,2,2-Trifluoro-N-(4-(hetroaryl)phenyl)acetamide derivatives via the reaction of 4-trifluoroacetamido-ω-bromoacetophenone derivatives with the appropriate thioamides or heterocyclic amine derivatives was achieved thermally as well as under microwave irradiation. The synthesized 2,2,2-trifluoro-N-(4-(hetroaryl)phenyl)acetamide derivatives offer an advantage of their easy and safe synthesis in a simple procedure from inexpensive starting materials and it is expected that they would be useful compounds with potentially high pharmacological and biological activities.
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