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Carbamoyl imines of methyl trifluoropyruvate in cyclocondensation and cycloaddition reactions
Journal of Fluorine Chemistry 201 (2017) 19–23
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Carbamoyl imines of methyl trifluoropyruvate in cyclocondensation and cycloaddition reactions
MARK
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Alexey Yu. Aksinenko , Tatyana V. Goreva, Tatyana A. Epishina, Sergey V. Trepalin, Vladimir B. Sokolov Institute of Physiologically Active Compounds of Russian Academy of Sciences, Severnyi pr. 1, Chernogolovka, Moscow region, 142432, Russia
A R T I C L E I N F O
A B S T R A C T
Keywords: Fluorinated heterocycles Cyclocondensation Cycloaddition
Dimethyl and morpholinyl carbamoyl imines of trifluoropyruvate 1a,b were synthesized and studied in cyclocondensation and cycloaddition reactions. Cyclocondensation of carbamoyl imines 1a,b with benzyl urea, benzamidine, 3-aminocrotonitryl, 6-aminouracil, and acetylacetone led to 5-membered trifluoromethylated heterocycles with an ureido substituent. The [2 + 4]-cycloaddition reactions of carbamoyl imines 1a,b were performed with dialkylcyan amines and cyclopentadiene. Formerly unknown carbamoyl imines 1a,b and their derivatives were characterized by NMR spectroscopy (1H, 13C, 19F) and elemental analysis.
1. Introduction Nitrogen and oxygen heterocycles represent an important class of compounds which are found in natural products as well as known drugs. These moieties are widely prevalent in pharmaceuticals, agrochemicals, and functional materials. For this reason, an introduction of heterocyclic skeleton to a known molecule or formation of a different heterocyclic skeleton of a known molecule became a continuous task for organic and medicinal chemistry. Within the scope of this common approach of combining two or more pharmacophore fragments in one molecule aimed at discovery of new drugs, it was proposed to modify known biologically active amines and amides to obtain reactive imines of polyfluoroketones and construct fluorinated heterocycles with biologically active residue of these amines [1–9]. In the case of dialkyl amines, it is necessary to form an intermediate structure with primary amino- or amido-group. One way of doing this is the transformation of amine into correspondent urea. The structural fragment of urea is present in many of a vital meaningful compounds and drugs. Examples of acyclic and cyclic ureas such as Phenacetamide [10], Phenytoin [11], Diethylcarbamazine [12], 5Fluorouracil [13], Ritonavir [14], Lizuride [15], Sertindole [16] are shown in Fig. 1. The appearance of the ureido-fragment allows the formation of polyfluoroketone imines and consequent cyclocondensation and cycloaddition reactions with appropriate compounds (see Fig. 2). Before applying this approach it is important to estimate its efficiency using simple and available dialkylamines such as dimethyl
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Corresponding author. E-mail address: [email protected] (A.Y. Aksinenko).
http://dx.doi.org/10.1016/j.jfluchem.2017.07.015 Received 3 February 2017; Received in revised form 5 May 2017; Accepted 27 July 2017 Available online 05 August 2017 0022-1139/ © 2017 Elsevier B.V. All rights reserved.
amine and morpholine. In this paper, we describe synthesis of new trifluoromethylated heterocycles derived from N-carbamoyl imines of trifluoropyruvate using an early developed cyclocondensation and cycloaddition methods. It should be noted that only a few methods for the synthesis of carbamoyl imines of polyfluororoketones have been described in the literature such as thermal decomposition of dioxazines – adducts of polyfluororoketones with cyanamides [17,18] or 5-dimethylamino-2-oxo-3,3-bis(trifluoromethyl)-3H-1,2,4-oxathiazole [19], and isomerization of 2- dimethylamino-2-isocyanatoperfluoropropane [20]. At the same time, there are no data on the synthesis of carbamoyl imines of trifluoropyruvates. 2. Results and discussion Dimethyl- and morpholinyl carbamoyl imines of trifluoropyruvate were obtained by the sequential addition of methyl trifluoropyruvate and SOCl2 to a suspension of dimethyl or morpholinyl urea in benzene solution of pyridine to a suspension of dimethyl or morpholinyl urea and pyridine in benzene. After removing Pyto a suspension of dimethyl or morpholinyl urea and pyridine in benzene%HCl from the reaction mixture by filtration, the desired imines were isolated by distillation (Scheme 1). Cyclocondensation of imines 1a,b was performed with 1,3-binucleophiles such as benzyl urea and benzamidine (N,N-binucleophiles), 3-aminocrotonitryl and 6-aminouracil (C,N-binucleophiles), and acetylacetone as C,O-binucleophile. In all cases, these reactions resulted in the formation of corresponding CF3-heterocycles 2-6 bearing an ureido
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while another nodal CHN carbon atom has a signal at 82.8 ppm; the bridge methylene carbon atoms showed signals in the range of 36–40 ppm, and finally, the signals of carbon atoms at double bond of the cycle were assigned to NCCH = 128.9 ppm and CCCH = 139.9 ppm. Scheme 1. Condensation of carbamoyl imines with trifluoropyruvate.
3. Conclusion moiety (Scheme 2). In the reactions of [2 + 4]-cycloaddition carbamoyl imines 1 react easily and exothermically as heterodienes with dialkylcyan amines. However, the reactivity of imines 1 as dienophiles in the reaction with cyclopentadiene was low and required a prolonged heating in a sealed ampoule (20 h at 80–90 °C) (Scheme 3). The spectral and analytical data of synthesized compounds 1-8 are in agreement with the proposed structures. The signals of substituents in 1H NMR spectra are in conformity with their usual appearance. In the 19 F NMR spectra, the observed signals of the trifluoromethyl groups appear in the region of −71 to −79 ppm that is characteristic range for such groups. 13C NMR spectra of 1 and 8 showed characteristic quartets at 118 ppm with the constant of spin–spin coupling (CSSC) 1 JCF = 278 Hz (1a,b) and at 124 ppm with 1JCF = 283 Hz (8a,b) for the CF3-atom and quartets at 150 ppm with 2JCF = 38 Hz for the C]Natom (1a,b) and at 67 ppm with 2JCF = 28 Hz for the CF3C-atom (8a,b). The signals of other 8a,b skeleton’s carbon atoms were assigned as follows: the signals at 32 ppm undoubtedly belong to a nodal (apical) CHCCF3 carbon atom because the middle-distance CSSC 3JCF = 2.2 Hz,
In the present work, first representatives of carbamoylimines of methyltrifluoropyruvate were synthesized and studied in cyclocondensation reactions with 1,3-binucleophiles and [2 + 4]-cycloaddition reactions with dienes and dienophiles. The elaborated approach represents a convenient route to exo- and endocyclic modification of ureas with 5- and 6-membered trifluoromethylated heterocycles and can find broad applications in medicinal chemistry. 4. Experimental 4.1. General The 1H, 13C, and 19F NMR spectra were recorded on Bruker DXP at 200, 50, and 188 MHz, respectively, in CDCl3 and Me2SO-d6 using tetramethylsilane as an internal standard and CCl3F as an external standard. Chemical shifts are reported in ppm units with the use of δ scale. Melting points were measured in open capillary tubes and are uncorrected. Scheme 2. Cyclocondensation of imines 1a,b with 1,3-binucleophiles.
Scheme 3. [2 + 4]-Cycloaddition reactions of carbamoyl imines 1.
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Fig. 1. Drugs containing urea fragments.
Fig. 2. Possible pathways of using biologically active secondary amines in the synthesis of heterocycles.
4.3.1. 3-[1-Benzyl-2,5-dioxo-4-(trifluoromethyl)imidazolidin-4-yl]-1,1dimethylurea (2a) To a solution of 3 mmol of benzylurea in 10 mL of acetonitrile while stirring at 20 °C was added 3 mmol of imine 1a. The reaction mixture was stirred for 2 h at 20 °C, then 0.1 g Et3N was added and the reaction mixture was refluxed for 2 h. After cooling down, the solvent was evaporated, and the residue was crystallized from chloroform. Yield 72%; mp 172–174 °C. 1H NMR (200 MHz, Me2SO-d6): δ 2.80 (s, 6H, CH3N), 4.54 (s, 2H, CH2), 7.23 (s, 5 H, CHAr), 7.58 (s, 1H, NH), 9.25 (s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 77.7 s. Calcd. for C14H15F3N4O3: C, 48.84, H, 4.39, N, 16.27. Found: C, 48.98, H, 4.03, N, 16.24.
4.2. General procedure for preparation of imines 1a,b To a mixture of 0.1 mol of urea in 50 mL of benzene, 0.2 mol of pyridine, 0.11 mol of methyl trifluoropyruvate was added under stirring at 20 °C during 30 min. Then, 0.1 mol of SOCl2 was added dropwise, and the mixture was stirred during 2 h. The formed precipitate was filtered off. After the solvent removal, the residue was fractionated for 1a,b.
4.2.1. Methyl 2-[(dimethylcarbamoyl)imino]-3,3,3-trifluoropropanoate (1a) Yield: 83%; bp 110–112 °C (20 Torr). 1H NMR (200 MHz, CDCl3): δ 2.89 (s, 3H, CH3N), 3.05 (s, 3H, CH3N), 3.93 (s, 3H, CH3O). 13C NMR (50 MHz, CDCl3): δ 35.6 (CH3N), 35.7 (CH3N), 54.0 (CH3O), 118.3 (q, 1 JCF = 278 Hz, CF3), 150.0 (q, 2JCF = 38 Hz, C]N), 158.2 (C]O), 159.5 (C]O). 19F NMR (188.29 MHz, CDCl3): δ − 71.0 (s). Calcd. for C7H9F3N2O3: C, 37.18, H, 4.01, N, 12.39. Found: C, 37.36, H, 4.06, N, 12.44.
4.3.2. N-[1-Benzyl-2,5-dioxo-4-(trifluoromethyl)imidazolidin-4-yl] morpholine-4-carboxamide (2b) Compound 2b was synthesized similarly to compound 2a from 3 mmol of benzyl urea and 3 mmol of imine 1b. Yield: 68%; mp 192–194 °C. 1H NMR (200 MHz, CDCl3): δ 3.30 −3.47 (m, 4H, CH2N), 3.57 −3.77 (m, 4H, CH2O), 4.72 (s, 2H, CH2Ph), 6.57 (s, 1H, NH), 7.18–7.42 (m, 5H, CHAr), 8.19 (s, 1H, NH). 19F NMR (188.29 MHz, CDCl3): δ − 79.4 s. Calcd. for C16H17F3N4O4: C, 49.74, H, 4.44, N, 14.50. Found: C, 49.92, H, 4.33, N, 14.44.
4.2.2. Methyl 3,3,3-trifluoro-2-[(morpholin-4-ylcarbonyl)imino]propanoate (1b) Yield 78%; bp 115–116 °C (1 Torr), mp 62–64 °C. 1H NMR (200 MHz, CDCl3): δ 3.23–3.33 (m, 2H, CH2N), 3.53–3.78 (m, 6H, CH2N + CH2O), 3.91(s, 3H, CH3O). 13C NMR (50 MHz, CDCl3): δ 43.1 (CH2N), 45.6 (CH2N), 54.1 (CH3O), 66.1 (CH2O), 66.5 (CH2O), 117.9 (q, 1JCF = 279 Hz, CF3), 150.9 (q, 2JCF = 38 Hz, C]N), 158.0 (C]O), 158.2 (C]O). 19F NMR (188.29 MHz, CDCl3): δ − 69.1 s. Calcd. for C9H11F3N2O4: C, 40.31, H, 4.13, N, 10.45. Found: C, 40.21, H, 4.19, N, 10.24.
4.4.1. 1,1-Dimethyl-3-[5-oxo-2-phenyl-4-(trifluoromethyl)-4,5-dihydro1H-imidazol-4-yl]urea (3a) To a solution of 2 mmol of benzamidine in 10 mL of acetonitrile while stirring at 20 °C was added 2 mmol of imine 1a. The reaction mixture was stirred at 20 °C for 2 h and the formed precipitate was filtered off yielding compound 3a. Yield: 74%; mp 232–234 °C. 1H NMR (200 MHz, Me2SO-d6): δ 2.82 21
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4.6.1. 3-[4-Acetyl-5-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydrofuran-3yl]-1,1-dimethylurea (6a) A solution of 2 mmol of acetylacetone, 2 mmol of imine 1a and 0.1 g of Et3N in 10 mL of acetonitrile was heated at 70 °C for 6 h. After evaporation of the solvent the residue was recrystallized from chloroform/hexane (1:1). Yield: 64%; mp 126–129 °C. 1H NMR (200 MHz, CDCl3): δ 2.40 (s, 3H, CH3C]O), 2.52 (s, 3H, CH3C), 2.93 (s, 6H, CH3N), 5.55 (s, 1H, NH). 19F NMR (188.29 MHz, CDCl3): δ − 75.5 s. Calcd. for C11H13F3N2O4: C, 44.90, H, 4.45, N, 9.52. Found: C, 44.69, H, 4.29, N, 9.29.
(s, 6 H, CH3N), 6.12 (s, 1H, NH), 7.28–7.55 (m, 3H, CHAr), 7.96 (d, 2 H, J = 7.1 Hz, CHAr), 11.68 (br. s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 78.9 s. Calcd. for C13H13F3N4O2: C, 49.68, H, 4.17, N, 17.83. Found: C, 49.80, H, 4.02, N, 17.62. 4.4.2. N-[5-Oxo-2-phenyl-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-4yl]morpholine-4-carboxamide (3b) Compound 3b was synthesized similarly to compound 3a from 2 mmol of benzamidine and 2 mmol of imine 1b. Yield: 83%; mp 252–253 °C. 1H NMR (200 MHz, Me2SO-d6): δ 3.20 −3.38 (m, 4H, CH2N), 3.46 − 3.65 (m, 4H, CH2O), 7.47–7.71 (m, 3H, CHAr), 7.85 (s, 1H, NH), 8.00 (d, 2H, J = 7.1 Hz, CHAr), 11.96 (br. s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 77.2 s. Calcd. for C15H15F3N4O3: C, 50.56, H, 4.24, N, 15.72. Found: C, 50.68, H, 4.44, N, 15.54.
4.6.2. N-[4-Acetyl-5-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydrofuran3-yl]morpholine-4-carboxamide (6b) Compound 6b was synthesized similarly to compound 6a from 2 mmol of acetylacteone and 2 mmol of imine 1b. Yield: 64%; mp 126–129 °C. 1H NMR (200 MHz, CDCl3): δ 2.41 (s, 3H, CH3C]O), 2.54 (s, 3H, CH3C), 3.31 −3.49 (m, 4H, CH2N), 3.63 −3.77 (m, 4H, CH2O), 5.66 (s, 1H, NH). 19F NMR (188.29 MHz, CDCl3): δ − 73.2 s. Calcd. for C13H15F3N2O5: C, 46.43, H, 4.50, N, 8.33. Found: C, 46.38, H, 4.25, N, 8.51.
4.5.1. 3-[4-Cyano-5-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1Hpyrrol-3-yl]-1,1-dimethylurea (4a) To a stirred solution of 2 mmol of 3-aminocrotonitrile in 10 mL of acetonitrile 2 mmol of imine 1a was added at 20 °C. Stirring was continued at 20 °C for 2 h and the formed precipitate was filtered off yielding compound 4a. Yield: 81%; mp 243–245 °C. 1H NMR (200 MHz, Me2SO-d6): δ 2.15 (s, 3H, CH3C), 2.83 (s, 6H, CH3N), 7.50 (s, 1H, NH), 11.09 (s, 1H, NH). 19 F NMR (188.29 MHz, Me2SO-d6): δ − 73.1 (s). Calcd. for C10H11F3N4O2: C, 43.48, H, 4.01, N, 20.28. Found: C, 43.62, H, 4.16, N, 20.34.
4.8. General procedure for preparation of oxadiazines 7a-d A mixture of 2 mmol of cyanamine and 2 mmol of imine 1a or 1b in 10 mL of anhydrous benzene was kept at 20 °C for 1 day. The benzene was evaporated and the residue was recrystallized from a hexanechloroform mixture (5:1) to give oxadiazines 7a-d. 4.8.1. Methyl 2,6-bis(dimethylamino)-4-(trifluoromethyl)-4H-1,3,5oxadiazine-4-carboxylate (7a) Yield: 83%; mp 105–107 °C. 1H NMR (200 MHz, CDCl3): δ 2.97 (s, 12H, CH3N), 3.79 (s, 3H, CH3O). 19F NMR (188.29 MHz, CDCl3): δ − 79.5 s. Calcd. for C10H15F3N4O3: C, 40.54, H, 5.10, N, 18.91. Found: C, 40.36, H, 5.29, N, 18.80.
4.5.2. N-[4-Cyano-5-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1Hpyrrol-3-yl]morpholine-4-carboxamide (4b) Compound 4b was synthesized similarly to compound 4a from 2 mmol of 3-aminocrotonitrile and 2 mmol of imine 1b. Yield: 79%; mp 244–246 °C (decomposition). 1H NMR (200 MHz, Me2SO-d6,): δ 2.18 (s, 3H, CH3C]O), 3.27 −3.43 (m, 4H, CH2N), 3.46 −3.66 (m, 4H, CH2O), 7.85 (s, 1H, NH), 11.18 (s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 73.1 s. Calcd. for C12H13F3N4O3: C, 45.29, H, 4.12, N, 17.60. Found: C, 45.21, H, 4.18, N, 17.36.
4.8.2. Methyl 2-(dimethylamino)-6-(piperidin-1-yl)-4-(trifluoromethyl)4H-1,3,5-oxadiazine-4-carboxylate (7b) Yield: 81%; mp 85–87 °C. 1H NMR (200 MHz, CDCl3): δ 1.48 − 1.70 (m, 6H, CH2), 2.97 (s, 6H, CH3N), 3.36 − 3.53 (m, 4H, CH2N), 3.79 (s, 3H, CH3O). 19F NMR (188.29 MHz, CDCl3): δ − 79.5 s. Calcd. for C13H19F3N4O3: C, 46.43, H, 5.69, N, 16.66. Found: C, 46.64, H, 5.52, N, 16.81.
4.6.1. 3-[1-Benzyl-2,4,6-trioxo-5-(trifluoromethyl)-2,3,4,5,6,7hexahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,1-dimethylurea (5a) To a stirred solution of 2 mmol of 6-amino-1-benzyluracil in 5 mL of DMF 2 mmol of imine 1a was added at 20 °C. Stirring was continued at 20 °C for 12 h and the solvent was evaporated. The residue was recrystallized from acetonitrile. Yield: 66%; mp 242–243 °C (decomposition). 1H NMR (200 MHz, Me2SO-d6): δ 2.83 (s, 6H, CH3N), 4.96 and 5.10 (AB system, 2H, JAB = 16.8 Hz, CH2), 7.15–7.26 (m, 2H, CHAr), 7.27–7.44 (m, 4H, NH + CHAr), 11.16 (s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 73.1 s. Calcd. for C17H16F3N5O4: C, 49.64, H, 3.92, N, 17.03. Found: C, 49.54, H, 3.78, N, 17.26.
4.8.3. Methyl 2-(diethylamino)-6-(morpholin-4-yl)-4-(trifluoromethyl)4H-1,3,5-oxadiazine-4-carboxylate (7c) Yield: 74%; mp 94–96 °C. 1H NMR (200 MHz, CDCl3): δ 1.14 (t, 3H, J = 7.1 Hz, CH3CH2), 3.31 (q, 2H, J = 7.1 Hz, CH3CH2), 3.38 −3.50 (m, 4H, CH2N), 3.64 −3.74 (m, 4H, CH2O), 3.76 (s, 3H, CH3O). 19F NMR (188.29 MHz, CDCl3): δ − 72.0 s. Calcd. for C14H21F3N4O4: C, 45.90, H, 5.78, N, 15.29. Found: C, 45.84, H, 5.82, N, 15.16. 4.8.4. Methyl 2-(morpholin-4-yl)-6-(piperidin-1-yl)-4-(trifluoromethyl)4H-1,3,5-oxadiazine-4-carboxylate (7d) Yield: 84%; mp 96–98 °C. 1H NMR (200 MHz, CDCl3): δ 1.48 −1.70 (m, 6H, CCH2C), 3.33 −3.52 (m, 8H, CH2N), 3.65 −3.77 (m, 4H, CH2O), 3.78 (s, 3H, CH3O). 19F NMR (188.29 MHz, CDCl3): δ − 72.1 s. Calcd. for C15H21F3N4O4: C, 47.62, H, 5.59, N, 14.81. Found: C, 47.44, H, 5.38, N, 14.66.
4.6.2. N-[1-Benzyl-2,4,6-trioxo-5-(trifluoromethyl)-2,3,4,5,6,7hexahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl]morpholine-4-carboxamide (5b) Compound 5b was synthesized similarly to compound 5a from 2 mmol of 6-amino-1-benzyluracil and 2 mmol of imine 1b. Yield: 72%; mp 247–249 °C (decomposition). 1H NMR (200 MHz, Me2SO-d6): δ 3.20 −3.40 (m, 4H, CH2N), 3.44 −3.70 (m, 4H, CH2O), 4.96 and 5.10 (AB system, 2H, JAB = 17.1 Hz, PhCH2), 7.12–7.27 (m, 2H, CHAr), 7.27–7.44 (m, 3H, CHAr), 7.77 (s, 1H, NH), 11.22 (s, 1H, NH), 12.14 (br. s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 70.9 s. Calcd. for C19H18F3N5O5: C, 50.33, H, 4.00, N, 15.45. Found: C, 50.44, H, 3.98, N, 15.12.
4.9. General procedure for preparation of methyl 2-(dialkylcarbamoyl)-3(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates 8a,b A solution of 2 mmol of cyclopentadiene, 2 mmol of imine 1a or 1b in 10 mL of CH2Cl2 was heated at 80–90 °C for 20 h in a sealed ampoule. After cooling down, the ampoule was opened and the solvent 22
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was evaporated. The residue was purified by column chromatography (silica gel, CH2Cl2/hexane, 1:1). [5]
4.9.1. Methyl 2-(dimethylcarbamoyl)-3-(trifluoromethyl)-2-azabicyclo [2.2.1]hept-5-ene-3-carboxylate (8a) Yield: 54%; colorless oil. 1H NMR (200 MHz, CDCl3): δ 2.39 (ddt, 1H, 2JCH = 17.1 Hz, 3JCH = 7.9 Hz, 4JCH = 1.8 Hz, CH2), 2.69 (ddt, 1H, 2JCH = 17.1 Hz, 3JCH = 7.3 Hz, 4JCH = 1.8 Hz, CH2), 2.86 (s, 6H, CH3N), 3.34 (q, 1H, 3JCH = 7.6, CH), 3.81 (s, 3H, CH3O), 5.13 (dt,1H, 3 JCH = 7.3 Hz, 4JCH = 2.1 Hz, CH), 5.79–5.90 (m, 1H, CH= ), 6.16 (dt,1H, 3JCH = 5.8 Hz, 4JCH = 2.1 Hz, CH= ). 13C NMR (50 MHz, CDCl3): δ 32.8 (q, 3JCF = 2.2 Hz, CHCCF3), 36.6 (CCH2C), 39.7 (CH3N), 53.4 (CH3O), 67.4 (q, 2JCF = 28 Hz, CHCCF3), 82.8 (CHN), 124.7 (q, 1 JCF = 283 Hz, CF3), 128.9 (CH= ), 139.9 (CH= ), 157.2 (NC]O), 170.8 (CC]O). 19F NMR (188.29 MHz, CDCl3): δ − 72.9 s. Calcd. for C12H15F3N2O3: C, 49.32, H, 5.17, N, 9.59. Found: C, 49.46, H, 5.36, N, 9.36.
[6]
[7]
[8]
[9]
[10]
4.9.2. Methyl 2-(morpholin-4-ylcarbonyl)-3-(trifluoromethyl)-2-azabicyclo [2.2.1]hept-5-ene-3-carboxylate (8b) Yield: 48%; colorless oil. 1H NMR (200 MHz, CDCl3): δ 2.41 (ddt, 1H, 2JCH = 17.3 Hz, 3JCH = 8.1 Hz, 4JCH = 2.1 Hz, CH2), 2.67 (d, br.d, 1H, 2JCH = 17.3 Hz, 3JCH = 6.3 Hz, CH2), 3.30 (q, 1H, 3JCH = 7.6, CH), 3.33 −3.42 (m, 4H, CH2N), 3.58 −3.67 (m, 4H, CH2O), 3.82 (s, 3H, CH3O), 5.13 (dt,1H, 3JCH = 7.3 Hz, 4JCH = 2.1 Hz, CH), 5.77–5.88 (m, 1H, CH]), 6.16 (dt,1H, 3JCH = 5.6 Hz, 4JCH = 2.1 Hz, CH = ). 13C NMR (50 MHz, CDCl3): δ 32.7 (q, 3JCF = 2.2 Hz, CHCCF3), 39.7 (CCH2C), 44.8 (CH2N), 53.4 (CH3O), 66.5 (CH2O), 67.0 (q, 2 JCF = 28 Hz, CHCCF3), 82.8 (CHN), 124.5 (q, 1JCF = 283 Hz, CF3), 128.7 (CH]), 139.9 (CH]), 156.5 (NC]O), 170.0 (CC]O). 19F NMR (188.29 MHz, CDCl3): δ − 74.9 s. Calcd. for C14H17F3N2O4: C, 50.30, H, 5.13, N, 8.38. Found: C, 50.44, H, 5.32, N, 8.18.
[11]
[12]
[13]
[14]
[15]
Acknowledgement This publication was supported in the part by the Russian Foundation for Basic Research (project number 16-03-00696).
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Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
Carbamoyl imines of methyl trifluoropyruvate in cyclocondensation and cycloaddition reactions
MARK
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Alexey Yu. Aksinenko , Tatyana V. Goreva, Tatyana A. Epishina, Sergey V. Trepalin, Vladimir B. Sokolov Institute of Physiologically Active Compounds of Russian Academy of Sciences, Severnyi pr. 1, Chernogolovka, Moscow region, 142432, Russia
A R T I C L E I N F O
A B S T R A C T
Keywords: Fluorinated heterocycles Cyclocondensation Cycloaddition
Dimethyl and morpholinyl carbamoyl imines of trifluoropyruvate 1a,b were synthesized and studied in cyclocondensation and cycloaddition reactions. Cyclocondensation of carbamoyl imines 1a,b with benzyl urea, benzamidine, 3-aminocrotonitryl, 6-aminouracil, and acetylacetone led to 5-membered trifluoromethylated heterocycles with an ureido substituent. The [2 + 4]-cycloaddition reactions of carbamoyl imines 1a,b were performed with dialkylcyan amines and cyclopentadiene. Formerly unknown carbamoyl imines 1a,b and their derivatives were characterized by NMR spectroscopy (1H, 13C, 19F) and elemental analysis.
1. Introduction Nitrogen and oxygen heterocycles represent an important class of compounds which are found in natural products as well as known drugs. These moieties are widely prevalent in pharmaceuticals, agrochemicals, and functional materials. For this reason, an introduction of heterocyclic skeleton to a known molecule or formation of a different heterocyclic skeleton of a known molecule became a continuous task for organic and medicinal chemistry. Within the scope of this common approach of combining two or more pharmacophore fragments in one molecule aimed at discovery of new drugs, it was proposed to modify known biologically active amines and amides to obtain reactive imines of polyfluoroketones and construct fluorinated heterocycles with biologically active residue of these amines [1–9]. In the case of dialkyl amines, it is necessary to form an intermediate structure with primary amino- or amido-group. One way of doing this is the transformation of amine into correspondent urea. The structural fragment of urea is present in many of a vital meaningful compounds and drugs. Examples of acyclic and cyclic ureas such as Phenacetamide [10], Phenytoin [11], Diethylcarbamazine [12], 5Fluorouracil [13], Ritonavir [14], Lizuride [15], Sertindole [16] are shown in Fig. 1. The appearance of the ureido-fragment allows the formation of polyfluoroketone imines and consequent cyclocondensation and cycloaddition reactions with appropriate compounds (see Fig. 2). Before applying this approach it is important to estimate its efficiency using simple and available dialkylamines such as dimethyl
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Corresponding author. E-mail address: [email protected] (A.Y. Aksinenko).
http://dx.doi.org/10.1016/j.jfluchem.2017.07.015 Received 3 February 2017; Received in revised form 5 May 2017; Accepted 27 July 2017 Available online 05 August 2017 0022-1139/ © 2017 Elsevier B.V. All rights reserved.
amine and morpholine. In this paper, we describe synthesis of new trifluoromethylated heterocycles derived from N-carbamoyl imines of trifluoropyruvate using an early developed cyclocondensation and cycloaddition methods. It should be noted that only a few methods for the synthesis of carbamoyl imines of polyfluororoketones have been described in the literature such as thermal decomposition of dioxazines – adducts of polyfluororoketones with cyanamides [17,18] or 5-dimethylamino-2-oxo-3,3-bis(trifluoromethyl)-3H-1,2,4-oxathiazole [19], and isomerization of 2- dimethylamino-2-isocyanatoperfluoropropane [20]. At the same time, there are no data on the synthesis of carbamoyl imines of trifluoropyruvates. 2. Results and discussion Dimethyl- and morpholinyl carbamoyl imines of trifluoropyruvate were obtained by the sequential addition of methyl trifluoropyruvate and SOCl2 to a suspension of dimethyl or morpholinyl urea in benzene solution of pyridine to a suspension of dimethyl or morpholinyl urea and pyridine in benzene. After removing Pyto a suspension of dimethyl or morpholinyl urea and pyridine in benzene%HCl from the reaction mixture by filtration, the desired imines were isolated by distillation (Scheme 1). Cyclocondensation of imines 1a,b was performed with 1,3-binucleophiles such as benzyl urea and benzamidine (N,N-binucleophiles), 3-aminocrotonitryl and 6-aminouracil (C,N-binucleophiles), and acetylacetone as C,O-binucleophile. In all cases, these reactions resulted in the formation of corresponding CF3-heterocycles 2-6 bearing an ureido
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while another nodal CHN carbon atom has a signal at 82.8 ppm; the bridge methylene carbon atoms showed signals in the range of 36–40 ppm, and finally, the signals of carbon atoms at double bond of the cycle were assigned to NCCH = 128.9 ppm and CCCH = 139.9 ppm. Scheme 1. Condensation of carbamoyl imines with trifluoropyruvate.
3. Conclusion moiety (Scheme 2). In the reactions of [2 + 4]-cycloaddition carbamoyl imines 1 react easily and exothermically as heterodienes with dialkylcyan amines. However, the reactivity of imines 1 as dienophiles in the reaction with cyclopentadiene was low and required a prolonged heating in a sealed ampoule (20 h at 80–90 °C) (Scheme 3). The spectral and analytical data of synthesized compounds 1-8 are in agreement with the proposed structures. The signals of substituents in 1H NMR spectra are in conformity with their usual appearance. In the 19 F NMR spectra, the observed signals of the trifluoromethyl groups appear in the region of −71 to −79 ppm that is characteristic range for such groups. 13C NMR spectra of 1 and 8 showed characteristic quartets at 118 ppm with the constant of spin–spin coupling (CSSC) 1 JCF = 278 Hz (1a,b) and at 124 ppm with 1JCF = 283 Hz (8a,b) for the CF3-atom and quartets at 150 ppm with 2JCF = 38 Hz for the C]Natom (1a,b) and at 67 ppm with 2JCF = 28 Hz for the CF3C-atom (8a,b). The signals of other 8a,b skeleton’s carbon atoms were assigned as follows: the signals at 32 ppm undoubtedly belong to a nodal (apical) CHCCF3 carbon atom because the middle-distance CSSC 3JCF = 2.2 Hz,
In the present work, first representatives of carbamoylimines of methyltrifluoropyruvate were synthesized and studied in cyclocondensation reactions with 1,3-binucleophiles and [2 + 4]-cycloaddition reactions with dienes and dienophiles. The elaborated approach represents a convenient route to exo- and endocyclic modification of ureas with 5- and 6-membered trifluoromethylated heterocycles and can find broad applications in medicinal chemistry. 4. Experimental 4.1. General The 1H, 13C, and 19F NMR spectra were recorded on Bruker DXP at 200, 50, and 188 MHz, respectively, in CDCl3 and Me2SO-d6 using tetramethylsilane as an internal standard and CCl3F as an external standard. Chemical shifts are reported in ppm units with the use of δ scale. Melting points were measured in open capillary tubes and are uncorrected. Scheme 2. Cyclocondensation of imines 1a,b with 1,3-binucleophiles.
Scheme 3. [2 + 4]-Cycloaddition reactions of carbamoyl imines 1.
20
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Fig. 1. Drugs containing urea fragments.
Fig. 2. Possible pathways of using biologically active secondary amines in the synthesis of heterocycles.
4.3.1. 3-[1-Benzyl-2,5-dioxo-4-(trifluoromethyl)imidazolidin-4-yl]-1,1dimethylurea (2a) To a solution of 3 mmol of benzylurea in 10 mL of acetonitrile while stirring at 20 °C was added 3 mmol of imine 1a. The reaction mixture was stirred for 2 h at 20 °C, then 0.1 g Et3N was added and the reaction mixture was refluxed for 2 h. After cooling down, the solvent was evaporated, and the residue was crystallized from chloroform. Yield 72%; mp 172–174 °C. 1H NMR (200 MHz, Me2SO-d6): δ 2.80 (s, 6H, CH3N), 4.54 (s, 2H, CH2), 7.23 (s, 5 H, CHAr), 7.58 (s, 1H, NH), 9.25 (s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 77.7 s. Calcd. for C14H15F3N4O3: C, 48.84, H, 4.39, N, 16.27. Found: C, 48.98, H, 4.03, N, 16.24.
4.2. General procedure for preparation of imines 1a,b To a mixture of 0.1 mol of urea in 50 mL of benzene, 0.2 mol of pyridine, 0.11 mol of methyl trifluoropyruvate was added under stirring at 20 °C during 30 min. Then, 0.1 mol of SOCl2 was added dropwise, and the mixture was stirred during 2 h. The formed precipitate was filtered off. After the solvent removal, the residue was fractionated for 1a,b.
4.2.1. Methyl 2-[(dimethylcarbamoyl)imino]-3,3,3-trifluoropropanoate (1a) Yield: 83%; bp 110–112 °C (20 Torr). 1H NMR (200 MHz, CDCl3): δ 2.89 (s, 3H, CH3N), 3.05 (s, 3H, CH3N), 3.93 (s, 3H, CH3O). 13C NMR (50 MHz, CDCl3): δ 35.6 (CH3N), 35.7 (CH3N), 54.0 (CH3O), 118.3 (q, 1 JCF = 278 Hz, CF3), 150.0 (q, 2JCF = 38 Hz, C]N), 158.2 (C]O), 159.5 (C]O). 19F NMR (188.29 MHz, CDCl3): δ − 71.0 (s). Calcd. for C7H9F3N2O3: C, 37.18, H, 4.01, N, 12.39. Found: C, 37.36, H, 4.06, N, 12.44.
4.3.2. N-[1-Benzyl-2,5-dioxo-4-(trifluoromethyl)imidazolidin-4-yl] morpholine-4-carboxamide (2b) Compound 2b was synthesized similarly to compound 2a from 3 mmol of benzyl urea and 3 mmol of imine 1b. Yield: 68%; mp 192–194 °C. 1H NMR (200 MHz, CDCl3): δ 3.30 −3.47 (m, 4H, CH2N), 3.57 −3.77 (m, 4H, CH2O), 4.72 (s, 2H, CH2Ph), 6.57 (s, 1H, NH), 7.18–7.42 (m, 5H, CHAr), 8.19 (s, 1H, NH). 19F NMR (188.29 MHz, CDCl3): δ − 79.4 s. Calcd. for C16H17F3N4O4: C, 49.74, H, 4.44, N, 14.50. Found: C, 49.92, H, 4.33, N, 14.44.
4.2.2. Methyl 3,3,3-trifluoro-2-[(morpholin-4-ylcarbonyl)imino]propanoate (1b) Yield 78%; bp 115–116 °C (1 Torr), mp 62–64 °C. 1H NMR (200 MHz, CDCl3): δ 3.23–3.33 (m, 2H, CH2N), 3.53–3.78 (m, 6H, CH2N + CH2O), 3.91(s, 3H, CH3O). 13C NMR (50 MHz, CDCl3): δ 43.1 (CH2N), 45.6 (CH2N), 54.1 (CH3O), 66.1 (CH2O), 66.5 (CH2O), 117.9 (q, 1JCF = 279 Hz, CF3), 150.9 (q, 2JCF = 38 Hz, C]N), 158.0 (C]O), 158.2 (C]O). 19F NMR (188.29 MHz, CDCl3): δ − 69.1 s. Calcd. for C9H11F3N2O4: C, 40.31, H, 4.13, N, 10.45. Found: C, 40.21, H, 4.19, N, 10.24.
4.4.1. 1,1-Dimethyl-3-[5-oxo-2-phenyl-4-(trifluoromethyl)-4,5-dihydro1H-imidazol-4-yl]urea (3a) To a solution of 2 mmol of benzamidine in 10 mL of acetonitrile while stirring at 20 °C was added 2 mmol of imine 1a. The reaction mixture was stirred at 20 °C for 2 h and the formed precipitate was filtered off yielding compound 3a. Yield: 74%; mp 232–234 °C. 1H NMR (200 MHz, Me2SO-d6): δ 2.82 21
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4.6.1. 3-[4-Acetyl-5-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydrofuran-3yl]-1,1-dimethylurea (6a) A solution of 2 mmol of acetylacetone, 2 mmol of imine 1a and 0.1 g of Et3N in 10 mL of acetonitrile was heated at 70 °C for 6 h. After evaporation of the solvent the residue was recrystallized from chloroform/hexane (1:1). Yield: 64%; mp 126–129 °C. 1H NMR (200 MHz, CDCl3): δ 2.40 (s, 3H, CH3C]O), 2.52 (s, 3H, CH3C), 2.93 (s, 6H, CH3N), 5.55 (s, 1H, NH). 19F NMR (188.29 MHz, CDCl3): δ − 75.5 s. Calcd. for C11H13F3N2O4: C, 44.90, H, 4.45, N, 9.52. Found: C, 44.69, H, 4.29, N, 9.29.
(s, 6 H, CH3N), 6.12 (s, 1H, NH), 7.28–7.55 (m, 3H, CHAr), 7.96 (d, 2 H, J = 7.1 Hz, CHAr), 11.68 (br. s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 78.9 s. Calcd. for C13H13F3N4O2: C, 49.68, H, 4.17, N, 17.83. Found: C, 49.80, H, 4.02, N, 17.62. 4.4.2. N-[5-Oxo-2-phenyl-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-4yl]morpholine-4-carboxamide (3b) Compound 3b was synthesized similarly to compound 3a from 2 mmol of benzamidine and 2 mmol of imine 1b. Yield: 83%; mp 252–253 °C. 1H NMR (200 MHz, Me2SO-d6): δ 3.20 −3.38 (m, 4H, CH2N), 3.46 − 3.65 (m, 4H, CH2O), 7.47–7.71 (m, 3H, CHAr), 7.85 (s, 1H, NH), 8.00 (d, 2H, J = 7.1 Hz, CHAr), 11.96 (br. s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 77.2 s. Calcd. for C15H15F3N4O3: C, 50.56, H, 4.24, N, 15.72. Found: C, 50.68, H, 4.44, N, 15.54.
4.6.2. N-[4-Acetyl-5-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydrofuran3-yl]morpholine-4-carboxamide (6b) Compound 6b was synthesized similarly to compound 6a from 2 mmol of acetylacteone and 2 mmol of imine 1b. Yield: 64%; mp 126–129 °C. 1H NMR (200 MHz, CDCl3): δ 2.41 (s, 3H, CH3C]O), 2.54 (s, 3H, CH3C), 3.31 −3.49 (m, 4H, CH2N), 3.63 −3.77 (m, 4H, CH2O), 5.66 (s, 1H, NH). 19F NMR (188.29 MHz, CDCl3): δ − 73.2 s. Calcd. for C13H15F3N2O5: C, 46.43, H, 4.50, N, 8.33. Found: C, 46.38, H, 4.25, N, 8.51.
4.5.1. 3-[4-Cyano-5-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1Hpyrrol-3-yl]-1,1-dimethylurea (4a) To a stirred solution of 2 mmol of 3-aminocrotonitrile in 10 mL of acetonitrile 2 mmol of imine 1a was added at 20 °C. Stirring was continued at 20 °C for 2 h and the formed precipitate was filtered off yielding compound 4a. Yield: 81%; mp 243–245 °C. 1H NMR (200 MHz, Me2SO-d6): δ 2.15 (s, 3H, CH3C), 2.83 (s, 6H, CH3N), 7.50 (s, 1H, NH), 11.09 (s, 1H, NH). 19 F NMR (188.29 MHz, Me2SO-d6): δ − 73.1 (s). Calcd. for C10H11F3N4O2: C, 43.48, H, 4.01, N, 20.28. Found: C, 43.62, H, 4.16, N, 20.34.
4.8. General procedure for preparation of oxadiazines 7a-d A mixture of 2 mmol of cyanamine and 2 mmol of imine 1a or 1b in 10 mL of anhydrous benzene was kept at 20 °C for 1 day. The benzene was evaporated and the residue was recrystallized from a hexanechloroform mixture (5:1) to give oxadiazines 7a-d. 4.8.1. Methyl 2,6-bis(dimethylamino)-4-(trifluoromethyl)-4H-1,3,5oxadiazine-4-carboxylate (7a) Yield: 83%; mp 105–107 °C. 1H NMR (200 MHz, CDCl3): δ 2.97 (s, 12H, CH3N), 3.79 (s, 3H, CH3O). 19F NMR (188.29 MHz, CDCl3): δ − 79.5 s. Calcd. for C10H15F3N4O3: C, 40.54, H, 5.10, N, 18.91. Found: C, 40.36, H, 5.29, N, 18.80.
4.5.2. N-[4-Cyano-5-methyl-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1Hpyrrol-3-yl]morpholine-4-carboxamide (4b) Compound 4b was synthesized similarly to compound 4a from 2 mmol of 3-aminocrotonitrile and 2 mmol of imine 1b. Yield: 79%; mp 244–246 °C (decomposition). 1H NMR (200 MHz, Me2SO-d6,): δ 2.18 (s, 3H, CH3C]O), 3.27 −3.43 (m, 4H, CH2N), 3.46 −3.66 (m, 4H, CH2O), 7.85 (s, 1H, NH), 11.18 (s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 73.1 s. Calcd. for C12H13F3N4O3: C, 45.29, H, 4.12, N, 17.60. Found: C, 45.21, H, 4.18, N, 17.36.
4.8.2. Methyl 2-(dimethylamino)-6-(piperidin-1-yl)-4-(trifluoromethyl)4H-1,3,5-oxadiazine-4-carboxylate (7b) Yield: 81%; mp 85–87 °C. 1H NMR (200 MHz, CDCl3): δ 1.48 − 1.70 (m, 6H, CH2), 2.97 (s, 6H, CH3N), 3.36 − 3.53 (m, 4H, CH2N), 3.79 (s, 3H, CH3O). 19F NMR (188.29 MHz, CDCl3): δ − 79.5 s. Calcd. for C13H19F3N4O3: C, 46.43, H, 5.69, N, 16.66. Found: C, 46.64, H, 5.52, N, 16.81.
4.6.1. 3-[1-Benzyl-2,4,6-trioxo-5-(trifluoromethyl)-2,3,4,5,6,7hexahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,1-dimethylurea (5a) To a stirred solution of 2 mmol of 6-amino-1-benzyluracil in 5 mL of DMF 2 mmol of imine 1a was added at 20 °C. Stirring was continued at 20 °C for 12 h and the solvent was evaporated. The residue was recrystallized from acetonitrile. Yield: 66%; mp 242–243 °C (decomposition). 1H NMR (200 MHz, Me2SO-d6): δ 2.83 (s, 6H, CH3N), 4.96 and 5.10 (AB system, 2H, JAB = 16.8 Hz, CH2), 7.15–7.26 (m, 2H, CHAr), 7.27–7.44 (m, 4H, NH + CHAr), 11.16 (s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 73.1 s. Calcd. for C17H16F3N5O4: C, 49.64, H, 3.92, N, 17.03. Found: C, 49.54, H, 3.78, N, 17.26.
4.8.3. Methyl 2-(diethylamino)-6-(morpholin-4-yl)-4-(trifluoromethyl)4H-1,3,5-oxadiazine-4-carboxylate (7c) Yield: 74%; mp 94–96 °C. 1H NMR (200 MHz, CDCl3): δ 1.14 (t, 3H, J = 7.1 Hz, CH3CH2), 3.31 (q, 2H, J = 7.1 Hz, CH3CH2), 3.38 −3.50 (m, 4H, CH2N), 3.64 −3.74 (m, 4H, CH2O), 3.76 (s, 3H, CH3O). 19F NMR (188.29 MHz, CDCl3): δ − 72.0 s. Calcd. for C14H21F3N4O4: C, 45.90, H, 5.78, N, 15.29. Found: C, 45.84, H, 5.82, N, 15.16. 4.8.4. Methyl 2-(morpholin-4-yl)-6-(piperidin-1-yl)-4-(trifluoromethyl)4H-1,3,5-oxadiazine-4-carboxylate (7d) Yield: 84%; mp 96–98 °C. 1H NMR (200 MHz, CDCl3): δ 1.48 −1.70 (m, 6H, CCH2C), 3.33 −3.52 (m, 8H, CH2N), 3.65 −3.77 (m, 4H, CH2O), 3.78 (s, 3H, CH3O). 19F NMR (188.29 MHz, CDCl3): δ − 72.1 s. Calcd. for C15H21F3N4O4: C, 47.62, H, 5.59, N, 14.81. Found: C, 47.44, H, 5.38, N, 14.66.
4.6.2. N-[1-Benzyl-2,4,6-trioxo-5-(trifluoromethyl)-2,3,4,5,6,7hexahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl]morpholine-4-carboxamide (5b) Compound 5b was synthesized similarly to compound 5a from 2 mmol of 6-amino-1-benzyluracil and 2 mmol of imine 1b. Yield: 72%; mp 247–249 °C (decomposition). 1H NMR (200 MHz, Me2SO-d6): δ 3.20 −3.40 (m, 4H, CH2N), 3.44 −3.70 (m, 4H, CH2O), 4.96 and 5.10 (AB system, 2H, JAB = 17.1 Hz, PhCH2), 7.12–7.27 (m, 2H, CHAr), 7.27–7.44 (m, 3H, CHAr), 7.77 (s, 1H, NH), 11.22 (s, 1H, NH), 12.14 (br. s, 1H, NH). 19F NMR (188.29 MHz, Me2SO-d6): δ − 70.9 s. Calcd. for C19H18F3N5O5: C, 50.33, H, 4.00, N, 15.45. Found: C, 50.44, H, 3.98, N, 15.12.
4.9. General procedure for preparation of methyl 2-(dialkylcarbamoyl)-3(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates 8a,b A solution of 2 mmol of cyclopentadiene, 2 mmol of imine 1a or 1b in 10 mL of CH2Cl2 was heated at 80–90 °C for 20 h in a sealed ampoule. After cooling down, the ampoule was opened and the solvent 22
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A.Y. Aksinenko et al.
was evaporated. The residue was purified by column chromatography (silica gel, CH2Cl2/hexane, 1:1). [5]
4.9.1. Methyl 2-(dimethylcarbamoyl)-3-(trifluoromethyl)-2-azabicyclo [2.2.1]hept-5-ene-3-carboxylate (8a) Yield: 54%; colorless oil. 1H NMR (200 MHz, CDCl3): δ 2.39 (ddt, 1H, 2JCH = 17.1 Hz, 3JCH = 7.9 Hz, 4JCH = 1.8 Hz, CH2), 2.69 (ddt, 1H, 2JCH = 17.1 Hz, 3JCH = 7.3 Hz, 4JCH = 1.8 Hz, CH2), 2.86 (s, 6H, CH3N), 3.34 (q, 1H, 3JCH = 7.6, CH), 3.81 (s, 3H, CH3O), 5.13 (dt,1H, 3 JCH = 7.3 Hz, 4JCH = 2.1 Hz, CH), 5.79–5.90 (m, 1H, CH= ), 6.16 (dt,1H, 3JCH = 5.8 Hz, 4JCH = 2.1 Hz, CH= ). 13C NMR (50 MHz, CDCl3): δ 32.8 (q, 3JCF = 2.2 Hz, CHCCF3), 36.6 (CCH2C), 39.7 (CH3N), 53.4 (CH3O), 67.4 (q, 2JCF = 28 Hz, CHCCF3), 82.8 (CHN), 124.7 (q, 1 JCF = 283 Hz, CF3), 128.9 (CH= ), 139.9 (CH= ), 157.2 (NC]O), 170.8 (CC]O). 19F NMR (188.29 MHz, CDCl3): δ − 72.9 s. Calcd. for C12H15F3N2O3: C, 49.32, H, 5.17, N, 9.59. Found: C, 49.46, H, 5.36, N, 9.36.
[6]
[7]
[8]
[9]
[10]
4.9.2. Methyl 2-(morpholin-4-ylcarbonyl)-3-(trifluoromethyl)-2-azabicyclo [2.2.1]hept-5-ene-3-carboxylate (8b) Yield: 48%; colorless oil. 1H NMR (200 MHz, CDCl3): δ 2.41 (ddt, 1H, 2JCH = 17.3 Hz, 3JCH = 8.1 Hz, 4JCH = 2.1 Hz, CH2), 2.67 (d, br.d, 1H, 2JCH = 17.3 Hz, 3JCH = 6.3 Hz, CH2), 3.30 (q, 1H, 3JCH = 7.6, CH), 3.33 −3.42 (m, 4H, CH2N), 3.58 −3.67 (m, 4H, CH2O), 3.82 (s, 3H, CH3O), 5.13 (dt,1H, 3JCH = 7.3 Hz, 4JCH = 2.1 Hz, CH), 5.77–5.88 (m, 1H, CH]), 6.16 (dt,1H, 3JCH = 5.6 Hz, 4JCH = 2.1 Hz, CH = ). 13C NMR (50 MHz, CDCl3): δ 32.7 (q, 3JCF = 2.2 Hz, CHCCF3), 39.7 (CCH2C), 44.8 (CH2N), 53.4 (CH3O), 66.5 (CH2O), 67.0 (q, 2 JCF = 28 Hz, CHCCF3), 82.8 (CHN), 124.5 (q, 1JCF = 283 Hz, CF3), 128.7 (CH]), 139.9 (CH]), 156.5 (NC]O), 170.0 (CC]O). 19F NMR (188.29 MHz, CDCl3): δ − 74.9 s. Calcd. for C14H17F3N2O4: C, 50.30, H, 5.13, N, 8.38. Found: C, 50.44, H, 5.32, N, 8.18.
[11]
[12]
[13]
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Acknowledgement This publication was supported in the part by the Russian Foundation for Basic Research (project number 16-03-00696).
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