Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2019, 84, 8976−8983
Synthesis of N‑Pyrrolyl(furanyl)-Substituted Piperazines, 1,4Dizepanes, and 1,4-Diazocanes Mateus Mittersteiner, Valquiria P. Andrade, Lucimara L. Zachow, Clarissa P. Frizzo, Helio G. Bonacorso, Marcos A. P. Martins, and Nilo Zanatta* Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Rio Grande do Sul, Brazil
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ABSTRACT: The synthetic potential of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one toward the catalyst-free synthesis of N-pyrrolyl(furanyl)-piperazines, 1,4-diazepanes, and 1,4-diazocanes through a telescoped protocol is reported. This threecomponent one-pot method provided 23 examples with high chemo- and regioselectivity at yields up to 96%.
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INTRODUCTION 1,4-Diazacycles and their derivatives belong to a heterocycle class that has been receiving much attention in the past few years because of exhibition of biological and pharmacological activities.1 These six-, seven-, and eight-membered heterocycle scaffolds have been reported to act as acetylcholinesterase inhibiting,2 anticonvulsant,3 anxiolytic,4 and anticancer5 agents. When combined with other scaffolds, such as pyrazoles, pyrazolines, and chalcones, these heterocycles have acted as antimalarial, antitrypanosomal, and antileishmanial agents.6 On the other hand, pyrroles and furan-containing molecules have been widely used as antifungal,7,8 antioxidant,9,10 antibacterial,11,12 anti-inflammatory,13,14 and antitumor agents.15 Even though the piperazine core is easily inserted into organic molecules (because of it being commercially available), the medium-sized seven- and eight-membered diaza rings are far less accessible. Although there are several synthetic pathways for preparing 1,4-diazepin-2-ones,16−18 there is a lack of efficient methodologies for preparing 1,4-diazepane/ diazocane cores. There are some interesting approaches regarding these cores that are worth highlighting; for example: reactions of 1,3-dielectrophiles, such as α,β-unsaturated ketones19 and their derivatives, with 1,2-phenylenediamine (Scheme 1a);20,21 and the Pictet−Spengler cyclization of 1,2ethanediamines with aldehydes.22 Chiral aziridines were also used as a successful pathway to piperazines, 1,4-diazepanes, and 1,4-diazocanes, through ring opening with amino alcohols (Scheme 1b). Although this methodology proved to be useful, the synthetic route is lengthy and requires protection/ deprotection steps, as well as the use of base.23 Therefore, the development of new, catalyst-free, and efficient single-step © 2019 American Chemical Society
synthetic routes for these scaffolds remains a challenge (Scheme 1c). 5-Bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one (enone 1) has been proved to be a successful building block for the synthesis of functionalized pyrazoles,24,25 enamino-phosphonates,26 dienes,27 and NH-pyrroles.28 Given that we have already demonstrated the synthesis of 4-amino-2-trifluoromethyl-1H-pyrroles from the reaction of enone 1 with primary amines,29 we expected that by using aliphatic diamines followed by the addition of a primary amine, symmetric bis4-amino-2-trifluoromethyl-1H-pyrroles would be obtained (Scheme 2, pathway 1). However, we unexpectedly observed spontaneous heterocyclization of the enamine group that was formed before the formation of the pyrroles (Scheme 2, pathway 2). Herein, we report the spontaneous cyclization of bis-5bromo-4-aminovinyl trifluoromethyl ketones as a direct pathway toward preparing piperazines, 1,4-diazepanes, and 1,4-diazocanes functionalized at the N4 position with pyrroles or furans, by controlling the reaction medium only.
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RESULTS AND DISCUSSION For the optimization of the reaction conditions, we considered enone 1 (2.0 equiv), 1,3-diaminopropane (1.0 equiv), and butylamine (variable amounts)see Table 1. The 1,3diaminopropane was chosen for this stage because of the possibility of preparing seven-membered heterocycles. The Received: March 27, 2019 Published: June 20, 2019 8976
DOI: 10.1021/acs.joc.9b00867 J. Org. Chem. 2019, 84, 8976−8983
Article
The Journal of Organic Chemistry Scheme 1. Selected Approaches for the Synthesis of 1,4-Diazacycles
Scheme 2. Addition of a Primary Amine to the Enamine Intermediate
Table 1. Optimization of the Reaction Conditions for the Synthesis of 4aa
a
entry
butylamine (equiv)
solvent
time (h)
temp (°C)
1 2 3 4 5 6 7 8 9 10 11 12 13
1 2 4 8 2 2 2 2 2 2 2 2 2
CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 THF MeCN EtOH
1.00 1.00 1.00 1.00 1.00 0.25 0.50 2.00 3.00 1.00 1.00 1.00 0.25
61 61 61 61 25 61 61 61 61 66 82 79 120
b
yield (%)b b
68 27b 23b b,c
49 55 65 67 50 c c c
c
Isolated yield after column chromatography. Mainly starting material was detected in TLC analysis. Formation of complex mixture of compounds. Reaction conditions: enone 1 (2 equiv), diamine 2a (1 equiv), solvent (10 mL).
addition of the diamine was performed at 0 °C in order to favor the addition at the 4-position rather than substitution at the 5-position of enone 1. For this step, 10 min of reaction was sufficient [monitored by thin layer chromatography (TLC)]. Several attempts were made to isolate the intermediate, but it
decomposed quickly; therefore, it was suitable for further reactions only when kept at 0 °C. Once this step was established, the second nitrogen nucleophile (butylamine) was added, and the reaction was heated to reflux to allow the cyclization of the pyrrole at the N4 position. 8977
DOI: 10.1021/acs.joc.9b00867 J. Org. Chem. 2019, 84, 8976−8983
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The Journal of Organic Chemistry
the anilines. When using anilines bearing electron-rich groups (3-OMe, 4-OMe, 4-Me), the desired products were obtained at moderate yields of 48−65%. For anilines fluorinated at the 3- or 4-position, the desired 4k and 4l were obtained at a yield of 56 and 50%, respectively. When the 4-Cl aniline was used, a lower yield (44%) was obtained. When an aniline with a stronger withdrawing group (e.g., 4-NO2) was used, the cyclocondensation reaction to form the N-aryl pyrrole did not occur, and only a complex mixture of compounds was formed. Despite this, all the targeted products were obtained at moderate (44%) to good (71%) yields. The reaction scope was very broad, furnishing products with alkyl and aryl groups bearing several substituents. In order to enhance our reaction scope and the usefulness of the methodology proposed herein, we explored the reaction of enone 1 with 1,4-diaminobutane (5), which led to 7a and 7b at yields of 55 and 60%, respectively. Piperazine rings were prepared by reacting enone 1 with 1,2-diaminoethane (6), and using the same conditions as for diamine 2 (Scheme 3). One can see that, when aryl amines were used in the second step of the reaction between enone 1 and 1,2-diaminoethane 6, the reaction performed well, furnishing the respective pyrrolylpiperazines 8. However, when alkyl amines were used, for the second reaction step, a mixture of the expected pyrrolylpiperazine 8 together with the respective furyl-piperazine 10 (see Scheme 4)resulting from the cyclocondensation of the enaminone intermediate in basic mediawas obtained at 30% (determined by 1H NMR). We speculate that the higher basicity of the alkyl amine combined with the high sensitivity of the piperazine intermediate led to this behavior. It is important to note that, under the same reaction condition, the 1,4-diazepane intermediate furnished the furyl derivative 9 at only 2%. The products 8 derived from the alkyl amines (propyl, butyl, and phenethyl) are not presented in this stage because it was not possible to separate the pyrrolyl-piperazines 8 from the respective furyl-piperazine 10. Several purification techniques (e.g., column chromatography with different eluents and recrystallization) were tested; however, the two compounds presented similar polarity and solubility properties; therefore, the separation did not occur. Thus, only pyrrolylpiperazines 8 derived from anilineswhich are far less basic than alkyl aminescould be prepared in this stage as pure compounds. When using EtOH as solvent for the synthesis of 4a (entry 12, Table 1), we detected an accentuated formation of the N4furyl derivative 9 over the N4-pyrrolyl derivative 4a (Scheme 3). Thus, we explored the synthesis of 9 and the aforementioned furyl derivatives as single products. Given that the furyl derivatives seem to be formed by a base-assisted reaction, butylamine acts as both base and nucleophile. To enlighten this, the reaction was carried out using Et3N (2 equiv)instead of butylaminein ethanol, under reflux for 1 h. Under these conditions, the furyl-diazepane 9 was obtained at 75% yield. When Na2CO3 (2 equiv) was used, the yield increased to 91%. The latter condition was also used for the reaction of the diamines 1,2-diaminoethane, and 1,4diaminobutane with enone 1, which furnished the furylpiperazine 10 (96% yield) and the furyl-diazocane 11 (89% yield), respectively (Scheme 4). Control experiments in the absence of base were conducted, and no product could be detected under the same experimental conditions. Lower yields were obtained when lower amounts of base were used, whereas the maximum yield
Common solvents reported for the synthesis of trifluoromethyl enaminones are CH2Cl2 and EtOH.30 However, when using EtOH, the formation of other byproducts was observed; therefore, we decided to perform the reactions in CHCl3, which was more suitable for the synthesis of 4a because of the higher reflux temperature that is usually required to induce the cyclocondensation reactions. Using the solvents THF and CH3CN led to lower yields and the formation of a complex mixture of products, respectively. The best conditions were achieved by using enone 1 (2 equiv) and 1,3-diaminopropane 2a (1 equiv), followed by the addition of butylamine 3 (2 equiv), under reflux conditions (61 °C) for 1 h. Several other conditionssuch as higher amounts of butylamine (entries 3 and 4 in Table 1) and a solvent-free procedure (entry 13 in Table 1)were tested to improve the isolated yield; however, a complex mixture of products was obtained in all cases. Longer reaction times also did not improve the yield of 4a (entries 8 and 9 in Table 1). With the optimal conditions in hand (entry 2 in Table 1), the substrate scope of the reaction proposed herein was subsequently explored by varying the amine used for the pyrrole cyclization (Figure 1). The reaction worked well with all amines tested, including anilines bearing several different substituents. It is important to note that the reaction with anilines required 3 h to be completed. Notably, aliphatic amines provided higher yields than the aromatic ones, probably because of the lower nucleophilicity of
Figure 1. Reaction scope for the synthesis of 4a−m. Conditions: enone 1 (2 equiv), diamine 2a (1 mmol), amines 3a−m (2 equiv), CHCl3 (10 mL). The ORTEP of compound 4h is shown, and the ellipsoids are drawn at the 50% probability level (CCDC: 1821111). 8978
DOI: 10.1021/acs.joc.9b00867 J. Org. Chem. 2019, 84, 8976−8983
Article
The Journal of Organic Chemistry Scheme 3. Synthesis of Piperazines and 1,4-Diazocanes from the Reaction of Enone 1 with Diamines 5 and 6
Scheme 4. Synthesis of 1,4-Diazaheterocycles N4Substituted with a Trifluoromethyl Furan
Scheme 5. Proposed Mechanism for the Formation of the N4-Pyrrolyl(furanyl)-Substituted 1,4-Diazacycles
was achieved at reflux for 30 min, for all of the diamines tested (Scheme 3). At room temperature, the reaction furnished lower yields in order to be feasible (16 h, 44% yield). A plausible mechanism for the synthesis of the compounds is presented in Scheme 5. Initially, the addition of the diamine molecule occurs at the 4-position of two molecules of enone 1, forming the intermediate I, which, by charge delocalization, eliminates two molecules of methanol, thus generating an enaminone-dimer (II). The intermediate II, in turn, intramolecularly attacks the enaminic nitrogen, which liberates HBr and provides the cyclic intermediate III. The pathway followed to form the pyrrole ring occurs by the nucleophilic substitution of bromine with the amine, with the bromine being captured by an amine molecule and stabilized as a quaternary ammonium salt. The allylic nitrogen attacks the carbonyl (IV), thus forming the cyclic intermediate V, which, by prototropism, eliminates one molecule of water and provides the compounds of the series 4, 7, and 8. For the furan pathway, the electron pair of the nitrogen delocalizes the charges and forms the nucleophilic oxygen, which is subjected to an intramolecular nucleophilic attack at the electrophilic center of the carbon bearing the bromine (III), thus forming the dihydrofuran derivative (VI). Baseassisted elimination of hydrogen from the dihydrofuran ring furnishes products 9, 10, and 11.
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CONCLUSIONS In summary, we developed a new, efficient, and direct synthetic route that enables the synthesis of piperazines, 1,4-diazepanes, and 1,4-diazocanessubstituted with trifluoromethyl pyrroles/furanthrough a three-component one-pot reaction. The methodology proposed herein has a wide reaction scope and furnishes moderate to high yields. These newly synthesized nitrogen heterocycles are excellent models for studies on biological and pharmacological activity.
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procedure for obtaining the enone 1 was described elsewhere.31,32 TLC was performed using silica gel plates F-254, 0.25 mm thickness. For visualization, TLC plates were either placed under ultraviolet light or stained with sulfuric vanillin followed by heating. Most reactions were monitored by TLC for disappearance of the starting material. 1H NMR spectra were recorded at 600 or at 400 MHz using TMS as the internal standard. Chemical shifts δ are quoted in parts per million (ppm), and coupling constants (J) are given in hertz (Hz). 13C NMR
EXPERIMENTAL SECTION
Reagents were purchased and used without further purification. Purification of final compounds was performed by flash chromatography using silica gel (230−400 mesh) as the stationary phase. The 8979
DOI: 10.1021/acs.joc.9b00867 J. Org. Chem. 2019, 84, 8976−8983
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The Journal of Organic Chemistry
Calcd for C16H17F6N3O: C, 50.40; H, 4.49; N, 11.02. Found: C, 49.98; H, 4.26; N, 10.79. (Z)-1,1,1-Trifluoro-3-(4-(1-benzyl-5-(trifluoromethyl)-1H-pyrrol3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4d). It was obtained as a yellow solid (297 mg, 69% yield), mp: 105−106 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 10.93 (br s, 1H), 7.35−7.30 (m, 3H), 7.10 (d, 2H, J = 8.4 Hz), 6.17 (d, 1H, J = 2.0 Hz), 6.11 (d, 1H, J = 2.2 Hz), 5.37 (s, 1H), 5.04 (s, 2H), 3.93 (s, 2H), 3.59 (q, 2H, J = 5.0 Hz), 3.45 (t, 2H, J = 5.2 Hz), 1.88−1.85 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.2 (q, 2JC−F = 31.3 Hz), 172.4, 136.6, 134.3, 128.8, 128.0, 127.2, 121.2 (q, 1JC−F = 264.2 Hz), 120.2 (q, 2JC−F = 37.1), 117.4 (q, 1JC−F = 286.7 Hz), 110.2, 100.8, 90.2, 55.8, 54.2, 51.4, 45.3, 25.7. 19F NMR (564 MHz, CDCl3): δ (ppm) −57.80, −76.75. MS (GC−MS, EI) m/z (%): 431 (68), 252 (12), 203 (53), 91 (100). Anal. Calcd for C20H19F6N3O: C, 55.69; H, 4.44; N, 9.74. Found: C, 55.31; H, 4.16; N, 9.48. (Z)-1,1,1-Trifluoro-3-(4-(1-phenethyl-5-(trifluoromethyl)-1H-pyrrol-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4e). It was obtained as a yellow solid (316 mg, 71% yield), mp: 105−106 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 10.94 (br s, 1H), 7.29 (t, 2H, J = 7.5 Hz), 7.25−7.22 (m, 1H), 7.09 (d, 2H, J = 8.3 Hz), 6.12 (d, 1H, J = 2.1 Hz), 5.95 (d, 1H, J = 2.2 Hz), 5.38 (s, 1H), 4.06 (t, 2H, J = 7.4 Hz), 3.87 (s, 2H), 3.6 (q, 2H, J = 5.3 Hz), 3.39 (t, 2H, J = 5.2 Hz), 2.98 (t, 2H, J = 7.6 Hz), 1.82−1.79 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.2 (q, 2JC−F = 33.0 Hz), 172.6, 137.9, 133.9, 128.8, 128.7, 126.8, 121.3 (q, 1JC−F = 265.5 Hz), 119.1 (q, 2 JC−F = 37.5 Hz), 117.5 (q, 1JC−F = 286.5) 110.6, 101.1, 90.0, 56.0, 54.4, 49.8, 45.3, 37.9, 25.9. 19F NMR (564 MHz, CDCl3): δ (ppm) −57.98, −76.81. MS (GC−MS, EI) m/z (%): 445 (100), 251 (12), 217 (20), 105 (47) 79 (11). Anal. Calcd for C21H21F6N3O: C, 56.53; H, 4.75; N, 9.43. Found: C, 56.25; H, 4.58; N, 9.35. (Z)-1,1,1-Trifluoro-3-(4-(1-(2,4-dichlorophenethyl)-5-(trifluoromethyl)-1H-pyrrol-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4f). It was obtained as a yellow solid (329 mg, 64% yield), mp 123−124 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 10.95 (br s, 1H), 7.38 (d, 1H, J = 2.1), 7.09 (dd, 1H, J = 8.2, 2.1 Hz), 6.88 (d, 1H, J = 8.2 Hz), 6.13 (d, 1H, J = 1.0 Hz), 5.95 (d, 1H, J = 1.6 Hz), 5.41 (s, 1H), 4.01 (t, 2H, J = 7.1 Hz), 3.91 (s, 2H), 3.58 (q, 2H, J = 5.2 Hz), 3.39 (t, 2H, J = 5.1), 3.10 (t, 2H, J = 7.2 Hz), 1.78−1.74 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.5 (q, 2JC−F = 31.5 Hz), 172.0, 134.8, 134.0, 133.5, 131.9, 129.4, 127.4, 121.2 (q, 1JC−F = 265.3 Hz), 119.4 (q, 2JC−F = 38.0 Hz), 117.4 (q, 1JC−F = 287.2 Hz), 111.0, 101.8, 90.1, 56.0, 54.7, 47.2, 45.3, 35.1, 25.5. 19F NMR (564 MHz, CDCl3): δ (ppm) −58.02, −76.80. MS (GC−MS, EI) m/z (%): 515 (65), 513 (100), 341 (15), 217 (31), 175 (27), 102 (17). Anal. Calcd for C21H19Cl2F6N3O: C, 49.04; H, 3.72; N, 8.17. Found: C, 48.79; H, 3.62; N, 8.38. (Z)-1,1,1-Trifluoro-3-(4-(1-phenyl-5-(trifluoromethyl)-1H-pyrrol3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4g). It was obtained as a yellow solid (263 mg, 63% yield), mp 134−135 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 10.98 (br s, 1H), 7.44−7.38 (m, 3H), 7.33− 7.32 (m, 2H), 6.34 (d, 1H, J = 2.4 Hz), 6.32 (d, 1H, J = 2.4 Hz), 5.47 (s, 1H), 4.01 (s, 2H), 3.63 (q, 2H, J = 5.3 Hz), 3.51 (t, 2H, J = 5.3 Hz), 1.94−1.89 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.3 (q, 2JC−F = 33.0 Hz), 172.2, 139.1, 134.7, 129.0, 128.3, 126.2, 120.8 (q, 2JC−F = 38.2 Hz), 120.9 (q, 1JC−F = 265.4 Hz), 117.5 (q, 1JC−F = 286.7 Hz), 111.6, 102.4 (q, 3JC−F = 3.3 Hz), 90.3, 55.8, 54.1, 45.3, 25.8. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.02, −76.75. MS (GC−MS, EI) m/z (%): 417 (100), 279 (52), 237 (18), 77 (10). Anal. Calcd for C19H17F6N3O: C, 54.68; H, 4.11; N, 10.07. Found: C, 54.42; H, 4.01; N, 10.25. (Z)-1,1,1-Trifluoro-3-(4-(1-(3-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrrol-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4h). It was obtained as golden crystals (290 mg, 65% yield), mp: 129−130 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 10.97 (br s, 1H), 7.31− 7.29 (m, 1H), 6.95−6.93 (m, 2H), 6.92−6.88 (m, 1H), 6.35 (d, 1H, J = 2.6 Hz), 6.32 (d, 1H, J = 2.7 Hz), 5.47 (s, 1H), 4.02 (s, 2H), 3.81 (s, 3H), 3.63 (q, 2H, J = 5.3 Hz), 3.51 (t, 2H, J = 5.4 Hz), 1.95−1.90 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 174.4 (q, 2 JC−F = 33.0 Hz), 172.2, 159.9, 140.1, 134.6, 129.7, 121−119 (CF3),
spectra were recorded at 150 MHz or at 100 MHz in CDCl3 solutions. 19F NMR spectra were recorded at 564 MHz, in CDCl3 using fluorobenzene as the external reference with the chemical shifts reported according to the CFCl3 standard. The low-resolution mass spectra were recorded on a GC−MS using EI mode (70 eV) and high-resolution mass spectra (HRMS) were recorded on an electrospray ionisation time-of-flight mass spectrometer. All melting points were determined on a melting point apparatus and are uncorrected. The CHN microanalyses were performed for all synthesized products, and they are within ±0.4 for all nuclei. Single-crystal X-ray diffraction was recorded in a diffractometer equipped with four-circles KAPPA goniometer, PHOTON 100 CMOS array detector, graphite monochromator, and Mo Kα (λ = 0.71073 Å) radiation source. The structure refinement was performed using the crystallographic software package WinGX from the SHELXS-97 and SHELXL-97 software. General Experimental Procedure for the Synthesis of 4, 7, and 8. To a stirring solution of 5-bromo-1,1,1-trifluoro-4methoxypent-3-en-2-one 1 (0.494 g, 2 mmol) in chloroform (10 mL), the corresponding diamine (1,2-diaminoethane, 1,3-diaminopropane or 1,4-diaminobutane, 1 mmol) was added at 0 °C. The reaction was kept under vigorous stirring at 0 °C for 10 min and the amine 3 was added (2 mmol for the aliphatic ones and 1.5 mmol for aryl amines). The mixture was heated to reflux for 1 or 3 h, for aliphatic and aryl amines, respectively. After this time, the mixture was filtered through a pad of SiO2 using CH2Cl2 as eluent. The solvent was removed under vacuum and the residue was recrystallized from hexane, providing the pure products. (Z)-1,1,1-Trifluoro-3-(4-(1-butyl-5-(trifluoromethyl)-1H-pyrrol-3yl)-1,4-diazepan-2-ylidene)propan-2-one (4a). It was obtained as a yellow solid (270 mg, 68% yield), mp: 108−109 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 10.97 (br s, 1H), 6.23 (s, 1H), 6.09 (s, 1H), 5.46 (s, 1H), 3.96 (s, 2H), 3.83 (t, 2H, J = 7.3 Hz), 3.61−3.60 (m, 2H), 3.46 (br s, 2H), 1.86 (br s, 2H), 1.70 (qui, 2H, J = 7.6 Hz), 1.31 (sext, 2H, J = 7.6 Hz), 0.91 (t, 3H, J = 7.4 Hz). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.1 (q, 2JC−F = 32.7 Hz), 172.8, 134.2, 124.0, 121.4 (q, 1JC−F = 264.8 Hz), 119.3 (q, 2JC−F = 37.9 Hz), 117.6 (q, 1JC−F = 287.4 Hz), 109.9, 100.4 (q, 3JC−F = 3.3 Hz), 90.2, 55.9, 54.3, 57.8, 45.3, 33.2, 25.8, 19.9, 13.5. 19F NMR (564 MHz, CDCl3): δ (ppm) −57.98, −76.81. MS (GC−MS, EI) m/z (%): 397 (100), 259 (11), 219 (12), 203 (16). Anal. Calcd for C17H21F6N3O: C, 51.38; H, 5.33; N, 10.57. Found: C, 51.24; H, 5.23; N, 10.88. (Z)-1,1,1-Trifluoro-3-(4-(1-propyl-5-(trifluoromethyl)-1H-pyrrol3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4b). It was obtained as a beige solid (191 mg, 50% yield), mp: 109−110 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 10.96 (br s, 1H), 6.22 (d, 1H, J = 1.9 Hz), 6.10 (d, 1H, J = 1.9 Hz), 5.45 (s, 1H), 3.96 (s, 2H), 3.80 (t, 2H, J = 6.8 Hz), 3.62−3.58 (m, 2H), 3.46 (t, 2H, J = 5.1 Hz), 1.88 (m, 2H), 1.75 (sext, 2H, J = 7.3 Hz), 0.90 (t, 3H, J = 7.4 Hz). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.2 (q, 2JC−F = 33.0 Hz), 172.7, 134.1, 121.2 (q, 1JC−F = 265.5 Hz), 119.5 (q, 2JC−F = 37.7 Hz), 117.5 (q, 1JC−F = 286.5 Hz), 109.9, 100.4 (q, 3JC−F = 3.2 Hz), 90.2, 56.0, 54.4, 49.6, 45.3, 25.9, 24.4, 11.1. 19F NMR (564 MHz, CDCl3): δ (ppm) −57.88, −76.77. MS (GC−MS, EI) m/z (%): 383 (100), 245 (26), 203 (26), 161 (10). Anal. Calcd for C16H19F6N3O: C, 50.13; H, 5.00; N, 10.96. Found: C, 50.33; H, 5.23; N, 11.20. (Z)-1,1,1-Trifluoro-3-(4-(1-allyl-5-(trifluoromethyl)-1H-pyrrol-3yl)-1,4-diazepan-2-ylidene)propan-2-one (4c). It was obtained as a pale yellow solid (266 mg, 70% yield), mp: 114−115 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 10.95 (br s, 1H), 6.21 (d, 1H, J = 2.2 Hz), 6.13 (d, 1H, J = 2.3 Hz), 5.93 (ddt, 1H, J = 17.0, 10.2, 5.8 Hz), 5.44 (s, 1H), 5.25 (dq, 1H, J = 10.2, 1.3 Hz), 5.14 (dq, 1H, J = 17.0, 1.6 Hz), 4.47 (dt, 2H, J = 5.8, 1.2 Hz), 3.96 (s, 2H), 3.60 (q, 2H, J = 5.0 Hz), 3.46 (t, 2H, J = 5.2 Hz), 1.88 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.3 (q, 2JC−F = 32.8 Hz), 172.5, 134.4, 133.1, 121.2 (q, 1JC−F = 265.1 Hz), 119.6 (q, 2JC−F = 37.8 Hz), 118.2, 117.6, 117.5 (q, 1JC−F = 287.2 Hz), 109.9, 100.9, 90.2, 55.9, 54.3, 50.4, 45.3, 26.0. 19F NMR (564 MHz, CDCl3): δ (ppm) −58.15, −76.87. MS (GC−MS, EI) m/z (%): 381 (100), 243 (10), 203 (70). Anal. 8980
DOI: 10.1021/acs.joc.9b00867 J. Org. Chem. 2019, 84, 8976−8983
Article
The Journal of Organic Chemistry
MHz, CDCl3): δ (ppm) 176.3 (q, 2JC−F = 33.3 Hz), 172.0, 137.6, 134.9, 134.2, 129.2, 127.5, 120.9 (q, 2JC−F = 38.2 Hz), 120.7 (q, 1JC−F = 267.1 Hz), 117.4 (q, 1JC−F = 288.7 Hz), 111.3, 102.7, 90.4, 55.7, 54.1, 45.3, 25.8. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.05, −76.77. Anal. Calcd for C19H16ClF6N3O: C, 50.51; H, 3.57; N, 9.30. Found: C, 50.34; H, 3.77; N, 9.57. (Z)-3-(4-(1-Benzyl-5-(trifluoromethyl)-1H-pyrrol-3-yl)-1,4-diazocan-2-ylidene)-1,1,1-trifluoropropan-2-one (7a). It was obtained as a yellow solid (245 mg, 55% yield), mp: 111−113 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 11.42 (br s, 1H), 7.36−7.29 (m, 3H), 7.16− 7.09 (m, 2H), 6.20 (d, 1H, J = 2.3 Hz), 6.08 (d, 1H, J = 2.1 Hz), 5.27 (s, 1H), 5.07 (s, 2H), 3.73−3.68 (m, 2H), 3.1−3.16 (m, 2H), 1.79− 1.75 (m, 4H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 175.6 (q, 2 JC−F = 33.0 Hz), 170.0, 136.9, 136.6, 128.8, 127.9, 126.9, 121.2 (q, 1 JC−F = 265.6 Hz), 120.4 (2JC−F = 37.6 Hz), 117.6 (q, 1JC−F = 286.2 Hz), 109.9, 103.7, 100.5 (q, 3JC−F = 3.6 Hz), 87.7, 53.7, 51.4, 50.6, 42.4, 29.1, 23.6. 19F NMR (564 MHz, CDCl3): δ (ppm) −57.75, −76.70. Anal. Calcd for C21H21F6N3O: C, 56.63; H, 4.75; N, 9.43. Found: C, 56.44; H, 4.55; N, 9.57. (Z)-3-(4-(1-phenethyl-5-(trifluoromethyl)-1H-pyrrol-3-yl)-1,4-diazocan-2-ylidene)-1,1,1-trifluoropropan-2-one (7b). It was obtained as a yellow solid (275 mg, 60% yield), mp: 120−121 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 11.45 (br s, 1H), 7.31−7.23 (m, 3H), 7.12−7.10 (m, 2H), 6.14 (d, 1H, J = 2.3 Hz), 5.91 (d, 1H, J = 2.2 Hz), 5.27 (s, 1H), 4.09 (t, 2H, J = 7.0 Hz), 3.93 (s, 2H), 3.69 (q, 2H, J = 7.0 Hz), 3.14 (t, 2H, J = 5.5 Hz), 3.01 (t, 2H, J = 7.3 Hz), 1.81− 1.69 (m, 4H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 175.5 (q, 2 JC−F = 33.0 Hz), 170.4, 137.9, 135.8, 128.8, 128.7, 126.8, 121.3 (q, 1 JC−F = 265.5 Hz), 119.2, (q, 2JC−F = 37.8 Hz), 117.7 (q, 1JC−F = 286.5 Hz), 109.6, 100.5 (3JC−F = 3.3 Hz), 87.5, 53.9, 50.7, 49.9, 42.3, 38.0, 29.0, 23.4. 19F NMR (564 MHz, CDCl3): δ (ppm) −57.91, −76.67. MS (GC−MS, EI) m/z (%): 459 (55), 307 (100), 231 (18), 105 (42). HRMS (ESI+) m/z: Calcd for C22H23F6N3O [M + H]+, 460.1824; found, 460.1822. (Z)-1,1,1-Trifluoro-3-(4-(1-phenyl-5-(trifluoromethyl)-1H-pyrrol3-yl)piperazin-2-ylidene)propan-2-one (8a). It was obtained as a salmon solid (242 mg, 60% yield), mp: 146−148 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 11.42 (br s), 7.47−7.42 (m, 3H), 7.37−7.35 (m, 2H), 6.46−6.44 (m, 2H), 5.31 (s, 1H), 3.86 (s, 2H), 3.65−3.62 (m, 2H), 3.31 (t, J = 5.7 Hz). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 175.9 (q, 2JC−F = 32.6 Hz), 166.1, 138.9, 136.5, 129.1, 128.6, 126.4, 121.6 (q, 2JC−F = 38.3 Hz), 120.7 (q, 1JC−F = 267.4 Hz) 117.5, (q, 1JC−F = 288.0 Hz, 112.9, 103.2, 85.7, 51.8, 47.2, 40.9. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.27, −76.75. MS (GC−MS, EI) m/ z (%): 403 (100), 238 (47), 167 (8), 77 (10). HRMS (ESI+) m/z: calcd for C18H15F6N3O [M + H]+, 404.1198; found, 404.1187. (Z)-1,1,1-Trifluoro-3-(4-(1-(4-methylphenyl)-5-(trifluoromethyl)1H-pyrrol-3-yl)piperazin-2-ylidene)propan-2-one (8b). It was obtained as a brown solid (258 mg, 62% yield), mp: 138−139 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 11.44 (br s, 1H), 7.24 (s, 4H), 6.44 (d, 1H, J = 1.9 Hz), 6.42 (d, 1H, J = 2.3 Hz), 5.31 (s, 1H), 3.85 (s, 2H), 3.65−3.62 (m, 2H), 3.30 (t, 2H, J = 5.6 Hz), 2.41 (s, 3H). 13 C{1H} NMR (150 MHz, CDCl3): δ (ppm) 175.9 (q, 2JC−F = 33.0 Hz), 166.2, 138.7, 136.4. 136.3, 129.7, 126.2, 121.6 (q, 2JC−F = 38.2 Hz), 120.7 (q, 1JC−F = 265.5 Hz), 117.57 (q, 1JC−F = 286.5 Hz), 113.0, 103.0 (q, 3JC−F = 2.8 Hz), 85.7, 51.9, 47.3, 40.9, 21.1. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.35, −76.72. MS (GC−MS, EI) m/z (%): 417 (100), 253 (18), 252 (35), 173 (7). HRMS (ESI+) m/z: calcd for C19H17F6N3O [M + H]+, 418.1355; found, 418.1362. (Z)-1,1,1-Trifluoro-3-(4-(1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrrol-3-yl)piperazin-2-ylidene)propan-2-one (8c). It was obtained as a brown solid (281 mg, 65% yield), mp: 147−149 °C. 1 H NMR (600 MHz, CDCl3): δ (ppm) 11.43 (br s, 1H), 7.27 (d, 2H, J = 9.1 Hz), 6.93 (d, 2 H, J = 8.8 Hz), 6.42 (s, 1H), 6.40 (s, 1H), 5.31 (s, 1H), 3.85 (s, 5H), 3.63 (br s, 2H), 3.30 (t, 2H, J = 5.5 Hz). 13 C{1H} NMR (150 MHz, CDCl3): δ (ppm) 175.9 (q, 2JC−F = 33.0 Hz), 166.1, 159.3, 136.3, 131.7, 127.8, 121.8 (q, 2JC−F = 38.0 Hz), 120.7 (q, 1JC−F = 267.1 Hz), 117.5 (q, 1JC−F = 286.5 Hz), 114.1, 113.2, 102.7 (q, 3JC−F = 3.2 Hz), 85.7, 55.5, 51.9, 47.3, 40.9. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.56, −76.73. MS (GC−MS, EI) m/
118.3, 114.3, 111.7, 111.4, 102.5 (q, 3JC−F = 3.4 Hz), 90.3, 55.7, 55.4, 54.1, 45.3, 25.8. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.05, −76.77. MS (GC−MS, EI) m/z (%): 447 (100), 309 (42), 269 (14). Anal. Calcd for C20H19F6N3O2: C, 53.69; H, 4.28; N, 9.39. Found: C, 53.48; H, 4.38; N, 9.30. (Z)-1,1,1-Trifluoro-3-(4-(1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrrol-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4i). It was obtained as a yellow solid (233 mg, 52% yield), mp: 130−132 °C.1H NMR (400 MHz, CDCl3): δ (ppm) 10.98 (br s, 1H), 7.25 (d, 2H, J = 9.2 Hz), 6.91 (d, 2H, J = 9.1 Hz), 6.30−6.28 (m, 2H), 5.46 (s, 1H), 4.01 (s, 2H), 3.84 (s, 3H), 3.63 (q, 2H, J = 5.3 Hz), 3.50 (t, 2H, J = 5.2 Hz), 1.94−1.89 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.4 (q, 2JC−F = 33.1 Hz), 172.2, 159.5, 134.5, 132.0, 130.0, 127.6, 123.2, 121.1 (q, 2JC−F = 38.2 Hz), 120.9 (q, 1JC−F = 265.5 Hz), 120.0, 117.5 (q, 1JC−F = 286.5 Hz), 114.5, 114.1, 112.0, 101.9 (q, 3 JC−F = 3.3 Hz), 90.3, 55.9, 55.5, 54.2, 45.27, 25.9. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.36, −76.77. MS (GC−MS, EI) m/z (%): 447 (100), 309 (32), 269 (12). Anal. Calcd for C20H19F6N3O2: C, 53.69; H, 4.28; N, 9.39. Found: C, 54.10; H, 4.32; N, 9.70. (Z)-1,1,1-Trifluoro-3-(4-(1-(4-methylphenyl)-5-(trifluoromethyl)1H-pyrrol-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4j). It was obtained as a yellow solid (207 mg, 48% yield), mp: 131−132 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 10.98 (br s, 1H), 7.21 (s, 4H), 6.31 (d, 2H, J = 2.3 Hz), 6.30 (d, 2H, J = 2.3 Hz), 5.46 (s, 1H), 4.01 (s, 2H), 3.63 (q, J = 5.0 Hz), 3.51 (t, J = 5.2 Hz), 2.39 (s, 3H), 1.94− 1.90 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.3 (2JC−F = 33.0 Hz), 172.3, 138.3, 136.6, 134.5, 129.6, 126.0, 120.9 (1JC−F = 265.5 Hz), 120.8 (q, 2JC−F = 38.3 Hz), 117.5 (1JC−F = 286.5 Hz), 111.8 (q, 4JC−F = 1.6 Hz), 102.1 (q, 3JC−F = 3.3 Hz), 90.3, 55.8, 54.1, 45.3, 25.8, 21.1. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.23, −76.84. MS (GC−MS, EI) m/z (%): 431 (100), 293 (46), 253 (13), 91 (8). Anal. Calcd for C20H19F6N3O: C, 55.69; H, 4.44; N, 9.74. Found: C, 56.09; H, 4.43; N, 10.02. (Z)-1,1,1-Trifluoro-3-(4-(1-(3-fluorophenyl)-5-(trifluoromethyl)1H-pyrrol-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4k). It was obtained as a pale green solid (244 mg, 56% yield), mp 169−170 °C. 1 H NMR (400 MHz, CDCl3): δ (ppm) 10.96 (br s, 1H), 7.39−7.38 (m, 1H), 7.15−7.08 (m, 3H), 6.33 (br s, 2H), 5.47 (s, 1H), 4.02 (s, 2H), 3.54 (q, 2H, J = 5.3 Hz), 3.52 (t, 2H, J = 5.2 Hz), 1.94−1.91 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.5 (q, 2JC−F = 33.2 Hz), 171.2, 162.5 (d, JC−F = 248.2 Hz), 140.3 (d, JC−F = 9.9 Hz), 134.9, 130.3 (d, JC−F = 8.9 Hz), 121.9, 121−117 (CF3), 115.3 (d, JC−F = 20.9 Hz), 113.8 (d, JC−F = 23.7 Hz), 111.2, 102.9 (q, 3JC−F = 3.35 Hz), 90.3, 55.7, 54.1, 45.3, 25.8. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.05, −76.81, −111.28. MS (GC−MS, EI) m/z (%): 435 (100), 297 (61), 255 (24), 95 (11). Anal. Calcd for C19H16F7N3O: C, 52.42; H, 3.70; N, 9.65. Found: C, 52.03; H, 3.74; N, 9.47. (Z)-1,1,1-Trifluoro-3-(4-(1-(4-fluorophenyl)-5-(trifluoromethyl)1H-pyrrol-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4l). It was obtained as a pale green solid (217 mg, 50% yield), mp: 121−122 °C. 1 H NMR (400 MHz, CDCl3): δ (ppm) 10.96 (br s, 1H), 7.31 (dd, 2H, J = 8.9, 4.8 Hz), 7.10 (t, 2H, J = 8.5 Hz), 6.31 (d, 1H, J = 2.2 Hz), 6.30 (d, 1H, J = 2.2 Hz), 5.46 (s, 1H), 4.02 (s, 2H), 3.64 (q, 2H, J = 5.3 Hz), 3.51 (t, 2H, J = 5.3 Hz), 1.93−1.91 (m, 2H). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.4 (q, 2JC−F = 33.0 Hz), 172.2, 162.2 (d, J = 248.0 Hz), 142.8, 135.1 (d, J = 3.1 Hz), 134.7, 128.2 (d, J = 8.7 Hz), 121.1 (q, 2JC−F = 38.3 Hz), 120.7 (q, 1JC−F = 265.5 Hz), 117.5 (q, 1JC−F = 286.5 Hz), 115.9 (d, J = 22.6 Hz), 111.7 (q, 4JC−F = 1.6 Hz), 102.4 (q, 3JC−F = 3.0 Hz), 90.4, 55.7, 54.1, 45.3, 25.8. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.23, −76.79, −112.89. MS (GC− MS, EI) m/z (%): 435 (100), 297 (66), 255 (24), 95 (13). Anal. Calcd for C19H16F7N3O: C, 52.42; H, 3.70; N, 9.65. Found: C, 52.23; H, 3.94; N, 9.57. (Z)-1,1,1-Trifluoro-3-(4-(1-(4-chlorophenyl)-5-(trifluoromethyl)1H-pyrrol-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (4m). It was obtained as a yellow solid (198 mg, 44% yield), mp: 127−129 °C. 1H NMR (600 MHz, CDCl3): δ (ppm) 10.96 (br s, 1H), 7.39 (d, 2H, J = 8.8 Hz), 7.27 (d, 2H, J = 8.6 Hz), 6.33 (d, 1H, J = 2.2 Hz), 6.30 (d, 1H, J = 2.3 Hz), 5.46 (s, 1H), 4.02 (s, 2H), 3.64 (q, 2H, J = 5.3 Hz), 3.52 (t, 2H, J = 5.3 Hz), 1.93−1.90 (m, 2H). 13C{1H} NMR (150 8981
DOI: 10.1021/acs.joc.9b00867 J. Org. Chem. 2019, 84, 8976−8983
Article
The Journal of Organic Chemistry z (%): 433 (100), 269 (15), 267 (28). HRMS (ESI+) m/z: calcd for C19H17F6N3O2 [M + H]+, 434.1304; found, 434.1304. (Z)-1,1,1-Trifluoro-3-(4-(1-(4-chlorophenyl)-5-(trifluoromethyl)1H-pyrrol-3-yl)piperazin-2-ylidene)propan-2-one (8d). It was obtained as a brown solid, (250 mg, 57% yield), mp: 148−149 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 11.42 (br s, 1H), 7.42 (d, 2H, J = 8.9 Hz), 7.30 (d, 2H, J = 8.5 Hz), 6.46 (d, 1H, J = 2.9 Hz), 6.40 (d, 1H, J = 2.3 Hz), 5.31 (s, 1H), 3.86 (s, 2H), 3.65−3.62 (m, 2H), 3.31 (t, 2H, J = 5.6 Hz). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.0 (q, 2JC−F = 33.1 Hz), 165.9, 138.7, 137.4, 136.8, 134.6, 129.3, 128.5, 127.7, 120.6 (q, 1JC−F = 285.7 Hz), 121.7 (q, 2JC−F = 38.3 Hz), 117.5 (q, 1JC−F = 286.0), 112.6, 103.5 (q, 3JC−F = 3.2 Hz), 85.7, 51.7, 47.2, 40.8. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.26, −76.76. MS (GC−MS, EI) m/z (%): 439 (35, M + 2) 437 (100), 274 (16), 272 (40). HRMS (ESI+) m/z: calcd for C18H14ClF6N3O [M + H]+, 438.0809; found, 438.0817. (Z)-1,1,1-Trifluoro-3-(4-(1-(4-bromophenyl)-5-(trifluoromethyl)1H-pyrrol-3-yl)piperazin-2-ylidene)propan-2-one (8e). It was obtained as a brown solid, (264 mg, 55% yield), mp: 121−123. 1H NMR (600 MHz, CDCl3): δ (ppm) 11.43 (br s, 1H), 7.58 (d, 2H, J = 8.7 Hz), 7.24 (d, 2H, J = 8.6 Hz), 6.47 (d, 1H, J = 2.1 Hz), 6.40 (d, 1H, J = 2.2 Hz), 5.31 (s, 1H), 3.86 (s, 2H), 3.65−3.63 (m, 2H), 3.31 (t, 2H, J = 5.4 Hz). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.0 (q, 2 JC−F = 33.0 Hz), 165.9, 137.8, 136.8, 132.3, 127.9, 122.6, 121.7 (q, 2 JC−F = 38.5 Hz), 120.6 (q, 1JC−F = 267.3 Hz), 117.5 (q, 1JC−F = 288.0 Hz), 112.6, 103.6 (q, 3JC−F = 3.3 Hz), 85.7, 51.7, 47.1, 40.8. 19F NMR (564 MHz, CDCl3): δ (ppm) −56.22, −76.78. MS (GC−MS, EI) m/ z (%): 483 (90, M + 2) 481 (100), 316 (35), 236 (14), 96 (10). HRMS (ESI+) m/z: calcd for C18H14BrF6N3O [M + H]+, 482.0303; found, 482.0301. General Experimental Procedure for the Synthesis of 9−11. To a stirring solution of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en2-one 1 (0.494 g, 2 mmol) in ethanol (10 mL), the corresponding diamine (1,2-diaminoethane, 1,3-diaminopropane or 1,4-diaminobutane, 1 mmol) was added at 0 °C. The reaction was kept under vigorous stirring at 0 °C for 10 min and Na2CO3 (2 mmol, 0.22 g) was added. The mixture was heated to reflux for 30 min. After this time, the solvent was removed under reduced pressure. The resulting solid was filtered through a pad of SiO2 using CH2Cl2 as eluent. The solvent was removed under vacuum and the residue was recrystallized from hexane, providing the pure 9−11 products. (Z)-1,1,1-Trifluoro-3-(4-(5-(trifluoromethyl)furan-3-yl)-1,4-diazepan-2-ylidene)propan-2-one (9). It was obtained as a beige solid (311 mg, 91% yield), mp: 119−120 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 10.89 (br s, 1H), 7.05 (d, 1H, J = 0.9 Hz), 6.55 (d, 1H, J = 0.9 Hz), 5.45 (s, 1H), 3.97 (s, 2H), 3.62 (q, 2H, J = 5.3 Hz), 3.48 (t, 2H, J = 5.3 Hz), 1.91−1.86 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ (ppm) 176.9 (q, 2JC−F = 33.9 Hz), 170.8, 141.7 (q, 2 JC−F = 42.8 Hz), 136.7, 127.4 (q, 4JC−F = 1.5 Hz), 118.8 (q, 1JC−F = 289.0 Hz), 117.3 (q, 1JC−F = 267.0 Hz), 104.8 (q, 3JC−F = 2.7 Hz), 89.9, 55.5, 54.2, 45.2, 26.1. 19F NMR (564 MHz, CDCl3): δ (ppm) −64.80, −76.95. MS (GC−MS, EI) m/z (%): 342 (100), 313 (12), 204 (40), 108 (9). Anal. Calcd for C13H12F6N2O2: C, 45.62; H, 3.53; N, 8.19. Found: C, 45.29; H, 3.39; N, 8.35. (Z)-1,1,1-Trifluoro-3-(4-(5-(trifluoromethyl)furan-3-yl)piperazin2-ylidene)propan-2-one (10). It was obtained as a beige solid (315 mg, 96% yield), mp: 117−119 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 11.43 (br s, 1H), 7.12 (d, 1H, J = 0.6 Hz), 6.66 (d, 1H, J = 1.1 Hz), 5.33 (s, 1H), 3.84 (s, 2H), 3.66−3.62 (m, 2H), 3.30 (t, 2H, J = 5.6 Hz). 13C{1H} NMR (150 MHz, CDCl3): δ (ppm) 176.3 (q, 2JC−F = 33.3 Hz), 164.9, 142.4 (q, 2JC−F = 42.9 Hz), 138.7, 128.5, 118.7 (q, 1 JC−F = 265.5 Hz), 117.4 (q, 1JC−F = 286.5 Hz), 110.1 (q, 3JC−F = 2.9 Hz), 105.2 (q, 3JC−F = 2.6 Hz), 85.8, 50.9, 46.6, 40.6. 19F NMR (564 MHz, CDCl3): δ (ppm) −64.84, −76.89. MS (GC−MS, EI) m/z (%): 328 (100), 163 (28), 96 (16). Anal. Calcd for C12H10F6N2O2: C, 43.91; H, 3.07; N, 8.54. Found: C, 44.10; H, 3.20; N, 8.69. (Z)-1,1,1-Trifluoro-3-(4-(5-(trifluoromethyl)furan-3-yl)-1,4-diazocan-2-ylidene)propan-2-one (11). It was obtained as a beige solid (316 mg, 89% yield), mp: 121−123 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 11.38 (br s, 1H), 7.00 (d, J =
