Abstract
Trifluoromethyl containing heterocycles are an integral part of many biologically active compounds in the agro and pharmaceutical chemistry. Herein, we report an efficient and concise three-step synthesis of 5-halo-6-trifluoromethylpyridine-3-carbonitriles from a trifluoroacetyl vinylogous enamine starting material. Hydrolysis furnishes the carboxylic acids.
The trifluoromethylpyridine structural motif has become a valuable component of research programs seeking molecules with useful biological activity. In the field of crop protection, this approach has met with significant success, with products now introduced as fungicides, herbicides and insecticides. For example, picoxystrobin is a fungicide introduced to the market in 2004 [1]; bicyclopyrone is a herbicide introduced in 2015 [2] and sulfoxaflor is an insecticide introduced to the market in 2013 [3] (Figure 1).
Selected commercial agrochemicals in crop protection.
The importance of functionalized trifluoromethylpyridines is further underlined by the continued appearance in the literature of complementary methods to prepare such building blocks [4], [5], [6], [7], [8], [9], [10], [11]. To facilitate the identification of new compounds with useful biological activity containing a trifluoromethylpyridine, we believe that a simple access to highly functionalized trifluoromethylpyridine intermediates which can be further elaborated, can be of value. In a previous communication [12], we have reported a simple three-step procedure to prepare 3,5-dicyano-6-trifluoromethylpyridine, together with the selective formation of a mono thioamide. In continuation of this theme, we now report an efficient synthesis of 5-halo-6-trifluoromethylpyridine-3-carbonitriles 1 from readily available starting materials. Hydrolysis of the nitriles then affords the corresponding nicotinic acids 2 (Figure 2).
5-Halo-6-trifluoromethyl nicotinic nitriles and acids.
At the outset of this work, a synthesis of the nicotinic nitriles 1 has not been known and only one of the nicotinic acids, 2b, has been reported [13] using 3-chloro-2-trifluoromethylpyridine, which has been prepared by the reaction of 3-chloro-2-iodopyridine with a source of nucleophilic CF3 in the presence of copper. In this approach, termed regioexhaustive functionalization, strong bases at low temperatures have been employed followed by treatment with iodine, then with magnesium and quenching with CO2 to form 2b in four steps from 3-chloro-2-iodopyridine.
In 1998, Cooke and co-workers [14] reported an efficient synthesis of 2-trifluoromethyl-5-cyanopyridine through the cyclization of the vinylogous enamine 5 with ammonium acetate. Compound 5 was prepared by the reaction of commercially available dimethylaminoacrylonitrile 3 with the vinyl ether 4 (Scheme 1).
Synthesis of 2-trifluoromethyl-5-cyanopyridine.
We first attempted to introduce halogen (chloro and bromo) at an early stage in the synthesis; conversion of the vinyl ether 4 into the halo derivatives 6 by halogenation and dehydrohalogenation has been reported [15]. However, all attempts to couple these vinyl ethers 6 with dimethylaminoacrylonitrile 3 were unsuccessful, with only complex mixtures resulting (Scheme 2).
Attempted synthesis of halogenated enamine 7.
We believe the lack of success of this approach may be due to reduced electrophilicity of the haloenones 6 compared to 4. Indeed, a steric hindrance between the halogen and the trifluoromethyl group in 6 has been postulated [15]; such an interaction could well reduce the conjugation between the double bond and the trifluoroacetyl group. To investigate this further, we compared 13C nuclear magnetic resonance (NMR) spectra of enone 4 and 6 (Hal=Br). Chemical shifts for C(3) and C(4) carbon are shown for compounds 4 and 6 (Hal=Br) in Figure 3. The chemical shift for C(4) in 6 (Hal=Br) is upfield compared to that for C(4) in 4, indicating a higher electron density at this position in 6 (Hal=Br). We believe this could explain the lack of success for the attempted reaction shown in Scheme 2. We then investigated the introduction of a halogen at a later stage in the synthesis and were pleased to find out that this approach was successful. We decided to first replace the dimethylamino leaving group by pyrrolidine and undertook some limited process studies to optimize the formation of the vinylogous system. Reaction of equimolar amounts of trans-3-pyrrolidine acrylonitrile [16] 8 and vinyl ether 4 in toluene at 100°C for 3 h gave the desired product 9 in only 34% yield. Significant amounts of two by-products were obtained, as shown in Scheme 3.
13C chemical shifts of C(3) and C(4) in 4 and 6.
Synthesis of trifluoroacetyl vinylogous enamine 9.
By-product 10 is formed by the self-condensation [17] of 8 and by-product 11 is presumably formed by the reaction of vinyl ether 4 with pyrrolidine liberated upon formation of 10. By increasing the amount of vinyl ether 4 to seven equivalents, product 9 was obtained in 85% yield; lower molar equivalents of 4 resulted in lower yields of 9. For the synthesis of halo-vinylogous enamines 12b–d, it was found that chlorination, bromination or iodination was best carried out at low temperatures, −50°C to 20°C in dichloromethane, using a 1.2–1.4 molar excess of sulfuryl chloride, bromine or N-iodosuccinimide, followed by the addition of 1.2 molar equivalents of triethylamine at −50°C. Compounds 12b–d were isolated after normal workup in good yields, and could be used without further purification. The stereochemistry around the diene system was not investigated; however, 19F NMR indicates the presence of only one isomer. Cyclisation of the vinylogous enamines 12b–d gave the pyridine derivatives 1b–d in good yields (Scheme 4).
Synthesis of 5-halo-6-trifluoromethyl nicotinic nitriles 1a–d.
Reagents and conditions: (i) 12b: SO2Cl2, DCM, −50°C, 0.5 h, then TEA, −50°C, 1 h; 12c: Br2, DCM, −50°C, 0.5 h, then TEA, −50°C, 1 h; 12d: NIS, DCM, 25°C, 2 h; (ii) NH4OAc, DMF, rt, 16 h; (iii) KF, sulfolane, 180°C, 4 h.
Rather than attempting the reaction of compound 9 with an electrophilic source of fluorine, we anticipated that a Halex type of reaction on pyridine 1b using potassium fluoride would lead to the formation of 1a, and were pleased to see this was the case, with 1a being formed in 58% yield after purification. Care should be taken when isolating 1a, as excessive drying under low pressure can lead to significant losses. Hydrolysis of the nitrile group under acidic or basic conditions then yielded the nicotinic acids 2a–d in good yields, isolated by column chromatography (Scheme 5).
Synthesis of 5-halo-6-trifluoromethyl nicotinic acids 2a–d.
In summary, the nucleophilic character of the readily prepared trifluoroacetyl vinylogous enamine system 9 was used to introduce halogen. Treatment of the resultant products 12b–d with ammonium acetate leads to 5-halo-6-trifluoromethyl nicotinic nitriles 1b–d in good yields. Such pyridine derivatives can be further developed, for example by Halex exchange to give the fluoro derivative 1a, or by hydrolysis to the corresponding nicotinic acids 2. All additional information and supporting data for all compounds reported is available in the online Appendix.
Experimental
All reagents were purchased and used as received. 1H NMR (400 MHz), 13C NMR (100 MHz) and 19F NMR (377 MHz) spectra were obtained using a Bruker Avance II-400 spectrometer in CDCl3 or DMSO-d6 solution. The HRMS analyses were performed on an Agilent QTOF 6520 mass spectrometer and LCMS analyses were conducted on a Thermo MSQ Plus mass spectrometer. IR spectra were recorded in KBr pellets on a Shimadzu DRS Prestige 21 instrument. Column chromatographic purifications were performed on a CombiFlashRf instrument (Teledyne Isco) using silica gel and mobile phases indicated below. Melting points were determined with a Mel-Temp-Electrothermal digital melting point apparatus and are uncorrected.
6,6,6-Trifluoro-5-oxo-2-(pyrrolidin-1-ylmethylene) hex-3-enenitrile (9)
The starting vinylogous enamine 9 was prepared adapting the literature procedure [14]. A solution of 3-pyrrolidin-1-ylprop-2-enenitrile (20.0 g, 164 mmol) and 4-ethoxy-1,1,1-trifluoro-3-butene-2-one (105 mL, 1.15 mol) in toluene (50 mL) was heated at 100°C for 3 h. The mixture was cooled to room temperature and diluted with cyclohexane (400 mL). The resulting precipitate was collected by filtration, washed with cyclohexane (120 mL) and dried to afford enamine 9 in 85% yield as pale yellow solid; mp 138–140°C; 1H NMR (CDCl3): δ 7.68 (d, 1H, J=14.5 Hz), 7.42 (s, 1H), 6.36 (d, 1H, J=14.5 Hz), 3.96 (br t, 2H, J=7 Hz), 3.69 (br t, 2H, J=7 Hz), 2.12 (quin, 2H, J=7 Hz), 1.99 (quin, 2H, J=7 Hz); 13C NMR (CDCl3): δ 178.8 (q, J=34 Hz), 155.0, 151.6, 121.3 (q, J=291 Hz), 107.1, 80.0, 55.4, 48.6, 25.7, 24.2; 19F NMR (CDCl3): δ −77.4 (s, 3F); IR: 3083, 2996, 2209, 1638, 1532, 1226, 1079, 825 cm−1. HRMS (ESI). Calcd for C11H11F3N2O: m/z 244.0823. Found: m/z 244.0820.
4-Chloro-6,6,6-trifluoro-5-oxo-2-(pyrrolidin-1-ylmethylene)hex- 3-enenitrile (12b)
Sulfuryl chloride (2.3 mL, 29 mmol) in dichloromethane (5 mL) was added dropwise to a solution of 6,6,6-trifluoro-5-oxo-2-(pyrrolidin-1-ylmethylene)hex-3-enenitrile (9) (6.1 g, 25 mmol) in dichloromethane (55 mL) at −50°C. The reaction mixture was stirred for 30 min till the complete consumption of starting material (1H NMR monitoring doublets of the alkene protons). Triethylamine (4.1 mL, 29 mmol) was added dropwise over a period of 5 min at −50°C. After 60 min, the mixture was diluted with dichloromethane (5 mL) and washed with aqueous 10% NaHCO3 (5 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated. Crude product was subjected to CombiFlash chromatography on silica gel with dichloromethane as mobile phase to afford enamine 12b in 70% yield as a pale yellow solid; mp 138–140°C; 1H NMR (DMSO-d6): δ 8.34 (s, 1H), 7.58 (s, 1H), 3.92 (t, 2H, J=7 Hz), 3.75 (t, 2H, J=7 Hz), 2.01 (quin, 2H, J=7 Hz), 1.85 (quin, 2H, J=7 Hz); 13C NMR (DMSO-d6): δ 171.6 (q, J=33 Hz), 160.6, 146.9, 121.6 (q, J=291 Hz), 117.4, 110.8, 76.9, 56.1, 48.7, 25.2, 23.4; 19F NMR (DMSO-d6): δ −67.2 (s, 3F); IR: 2996, 2948, 2928, 2206, 1675, 1623, 1539, 1444, 1261, 1124, 861 cm−1. HRMS (ESI). Calcd for C11H10ClF3N2O: m/z 278.0434. Found: m/z 278.0434.
4-Bromo-6,6,6-trifluoro-5-oxo-2-(pyrrolidin-1-ylmethylene)hex-3-enenitrile (12c)
Bromine (0.6 mL, 12.0 mmol) in dichloromethane (3.0 mL) was added dropwise to a solution of 6,6,6-trifluoro-5-oxo-2-(pyrrolidin-1-ylmethylene)hex-3-enenitrile (9, 2.5 g, 10 mmol) in dichloromethane (12 mL) at −50°C. The mixture was stirred for 30 min till the complete consumption of starting material (1H NMR monitoring doublets of the alkene protons). Triethylamine (1.7 mL, 12 mmol) was added dropwise over a period of 5 min at −50°C. After 60 min, the mixture was diluted with dichloromethane (20 mL) and washed with aqueous 10% NaHCO3 (5 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated. Crude product was subjected to CombiFlash chromatography on silica gel with dichloromethane–MeOH, 9.8:0.2 as mobile phase to afford enamine 12c in 74% yield as a pale yellow solid; mp 93°C; 1H NMR (DMSO-d6): δ 8.36 (s, 1H), 7.71 (s, 1H), 3.92 (br t, 2H, J=7 Hz), 3.75 (t, 2H, J=7 Hz), 2.01 (quin, 2H, J=7 Hz), 1.85 (quin, 2H, J=7 Hz); 13C NMR (DMSO-d6): δ 172.0 (q, J=33 Hz), 161.3, 149.6, 121.1 (q, J=292 Hz), 117.4, 101.7, 78.6, 56.4, 49.1, 25.4, 23.6; 19F NMR (DMSO-d6): δ −66.5 (s, 3F); IR: 2998, 2880, 2204, 1683, 1623, 1559, 1117, 862 cm−1. HRMS (ESI). Calcd for C11H10BrF3N2O: m/z 321.9929. Found: m/z 321.9939.
6,6,6-Trifluoro-4-iodo-5-oxo-2-(pyrrolidin-1-ylmethylene)hex-3-enenitrile (12d)
N-Iodosuccinimide (2.7 g, 12 mmol) was added to a solution of 6,6,6-trifluoro-5-oxo-2-(pyrrolidin-1-ylmethylene)hex-3-enenitrile (9, 2.5 g, 10 mmol) in dichloromethane (20 mL) at room temperature. The mixture was stirred for 2 h, diluted with dichloromethane (20 mL) and washed with aqueous 10% Na2S2O3 (10 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated. Crude product was subjected to CombiFlash chromatography on silica gel eluting with cyclohexane-EtOAc, 6:4, as mobile phase to afford enamine 12d in 70% yield as a yellow solid; mp 124–126°C; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.47–7.33 (m, 1H), 4.02 (br t, 2H, J=7 Hz), 3.75 (t, 2H, J=7 Hz), 2.12 (quin, 2H, J=7 Hz), 1.99 (quin, 2H, J=7 Hz); 13C NMR (CDCl3): δ 174.9 (q, J=33 Hz), 158.3, 152.1, 116.8, 115.9 (q, J=293 Hz), 82.5, 81.4, 56.4, 49.4, 25.8, 24.01; 19F NMR (CDCl3): δ −66.6 (s, 3F); IR: 3000, 2925, 2202, 1621, 1545, 1226.78, 1108, 862 cm−1. HRMS (ESI). Calcd for C11H10F3IN2O: m/z 369.9790. Found: m/z 369.9788.
5-Fluoro-6-(trifluoromethyl)pyridine-3-carbonitrile (1a)
To a solution of 5-chloro-6-(trifluoromethyl) pyridine-3-carbonitrile (1b) (1.8 g, 9 mmol) in sulfolane (11 mL) was added anhydrous potassium fluoride (1.3 g, 22 mmol) at room temperature. The mixture was heated to 180°C for 4 h, then cooled to room temperature and directly purified by column chromatography eluting with cyclohexane-EtOAc, 9:1, to afford product 1a in 58% yield as a yellow oil; 1H NMR (CDCl3): δ 8.79 (s, 1H), 7.94 (dd, 1H, J=9 Hz and 1 Hz); 13C NMR (CDCl3): δ 157.4 (d, J=274 Hz), 147.3 (d, J=6 Hz), 139.6 (dq, J=12 Hz and 37 Hz), 129.1 (d, J=22 Hz), 121.1 (dq, J=5 Hz and 274 Hz), 114.5 (d, J=4 Hz), 113.8; 19F NMR (CDCl3): δ −66.2 (s, 3F), −118.7 (s, 1F); IR: 3080, 3026, 2243, 1609, 1572, 1325, 1210, 1150, 1060, 906 cm−1; GCMS (EI): m/z 189.9, [M+].
General procedure for preparation of 5-halo-6-trifluoromethyl nicotinic nitriles 1b–d
Enamine 12b–d (2.0 g, 5 mmol) was dissolved in N,N-dimethylformamide (14 mL), and the solution was treated with ammonium acetate (2.5 g, 23 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. After complete conversion of the starting material the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography on silica gel eluting with cyclohexane-EtOAc, 9:1, to afford the product 1b–d.
5-Chloro-6-(trifluoromethyl)pyridine-3-carbonitrile (1b)
White solid; yield 52%; mp 43–44°C; 1H NMR (CDCl3): δ 8.87–8.82 (m, 1H), 8.20–8.17 (m, 1H); 13C NMR (CDCl3): δ 148.9, 148.3 (q, J=35 Hz), 142.5, 131.1, 121.5 (q, J=276 Hz), 114.0, 113.7; 19F NMR (CDCl3): δ −66.7 (s, 3F); IR: 3072, 2243, 1872, 1730, 1581, 1537, 1460, 1323, 1388, 1396, 1163, 1043, 925 cm−1. HRMS (ESI). Calcd for C7H2ClF3N2: m/z 206.9937. Found: m/z 206.9934.
5-Bromo-6-(trifluoromethyl)pyridine-3-carbonitrile (1c)
White solid; yield 63%; mp 88–90°C; 1H NMR (CDCl3): δ 8.88 (s, 1H), 8.37 (s, 1H); 13C NMR (CDCl3): δ 148.3, 147.9 (q, J=36 Hz), 144.9, 120.6 (q, J=276 Hz), 117.3, 118.8, 112.9, 112.7; 19F NMR (CDCl3): δ −66.7 (s, 3F); IR: 3070, 2949, 2243, 1892, 1585, 1529, 1454, 1375, 1321, 1209, 1037, 939 cm−1. HRMS (ESI). Calcd for C7H2BrF3N2: m/z 250.9425. Found: m/z 250.9426.
5-Iodo-6-(trifluoromethyl)pyridine-3-carbonitrile (1d)
White solid; yield 73%; mp 126–128°C; 1H NMR (CDCl3): δ 8.90 (d, 1H, J=1.6 Hz), 8.62 (d, 1H, J=1.6 Hz); 13C NMR (CDCl3): δ 152.5, 151.8 (q, J=35 Hz), 149.7, 124.5 (q, J=277 Hz), 113.7, 113.2, 88.1; 19F NMR (CDCl3): δ −66.5 (s, 3F); IR: 3060, 3011, 2942, 2245, 1891, 1577, 1324, 1207, 1396, 1164, 1033, 938 cm−1. HRMS (ESI). Calcd for C7H2F3IN2: m/z 297.9215. Found: m/z 297.9220.
General procedure for prepration of 5-halo-6-trifluoromethyl nicotinic acids 2a–d
A suspension of pyridine 1a–d (0.4 g, 2 mmol) in 10 N HCl (1.2 mL) was heated at 100°C for 3 h. The reaction mixture was cooled to room temperature and pH of mixture was increased to 4–5 using aqueous 10% sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (3×8 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash chromatography on silica gel eluting with cyclohexane-EtOAc, 7:3, to afford the desired product 2a–d.
5-Fluoro-6-(trifluoromethyl)pyridine-3-carboxylic acid (2a)
White solid; yield 56%; mp 102–104°C; 1H NMR (DMSO-d6): δ 9.00 (s, 1H), 8.41 (d, 1H, J=11 Hz); 13C NMR (DMSO-d6): δ 164.2, 157.8 (d, J=267 Hz), 145.8 (d, J=5 Hz), 136.8 (dd, J=12 Hz and 35 Hz), 132.8 (d, J=4 Hz), 127.3 (d, J=20 Hz), 121.9 (dq, J=5 Hz and 274 Hz); 19F NMR (DMSO-d6): δ −64.7 (s, 3F), −123.0 (q, J=15 Hz, 1F); IR: 3514, 3254, 2505, 1913, 1712, 1485, 1425, 1329, 1315, 1227, 1159, 1060, 923 cm−1. HRMS (ESI). Calcd for C7H3F4NO2: m/z 209.0100. Found: m/z 209.0100.
5-Chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid (2b)
White solid; yield 70%; mp 108–110°C; 1H NMR (CDCl3): δ 11.00 (br s, 1H), 9.25 (s, 1H), 8.56 (s, 1H); 13C NMR (CDCl3): δ 167.9, 148.6 (q, J=35 Hz), 147.9, 141.2, 130.9, 128.8, 121.8 (q, J=276 Hz); 19F NMR (CDCl3): δ −66.5 (s, 3F); IR (KBr): 3215, 2522, 1866, 1737, 1693, 1467, 1392, 1317, 1165, 1120, 1047, 889 cm−1. HRMS (ESI). Calcd for C7H3ClF3NO2: m/z 224.9804. Found: m/z 224.9807.
5-Bromo-6-(trifluoromethyl)pyridine-3-carboxylic acid (2c)
White solid; yield 97%; mp 196–198°C; 1H NMR (CDCl3): δ 11.78 (br s, 1H), 9.29 (s, 1H), 8.75 (s, 1H); 13C NMR (CDCl3): δ 167.9, 150.0 (q, J=34.0 Hz), 148.4, 144.7, 128.6, 122.0 (q, J=276 Hz), 118.3; 19F NMR (CDCl3): δ −66.4 (s, 3F). IR: 3215, 3080, 2873, 2522, 1737, 1686, 1693, 1392, 1317, 1170, 1045, 702 cm−1. HRMS (ESI). Calcd for C7H3BrF3NO2: m/z 268.9299. Found: m/z 268.9301.
5-Iodo-6-(trifluoromethyl)pyridine-3-carboxylic acid (2d)
White solid; yield 70%; mp 148–150°C; 1H NMR (CDCl3): δ 10.35 (br s, 1H), 9.33–9.28 (m, 1H), 9.01 (s, 1H); 13C NMR (CDCl3): δ 167.8, 153.1 (q, J=34 Hz), 151.8, 149.1, 128.5, 122.4 (q, J=277 Hz), 88.4; 19F NMR (CDCl3): δ −66.2 (s, 3F); IR: 3200, 3067, 2511, 2359, 2342, 1740, 1686, 1396, 1317, 1165, 1031, 756 cm−1. HRMS (ESI). Calcd for C7H3F3INO2: m/z 316.9273. Found: m/z 316.9237.
Acknowledgments
The authors would like to thank Syngenta Biosciences Private Ltd. for providing support in carrying out this work under the PhD program. This work has been carried out as a part of the PhD thesis (C. Manjunath) affiliated to the University of Goa. We acknowledge the experimental skill of our colleague, Michael Fruehauf, who is now sadly deceased.
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