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Synthesis of trifluoromethyl group bearing indoline-based heterocyclic systems and their application for the detection of cyanide
Journal of Fluorine Chemistry 182 (2016) 34–40
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Synthesis of trifluoromethyl group bearing indoline-based heterocyclic systems and their application for the detection of cyanide Greta Ragaite˙ a, Migle˙ Dagiliene˙ a, Sonata Kriksˇtolaityte˙ b, Vytas Martynaitis b, Algirdas Sˇacˇkus a,b,* a b
Institute of Synthetic Chemistry, Kaunas University of Technology, Radvile˙nu˛ pl. 19, LT-50254 Kaunas, Lithuania Department of Organic Chemistry, Kaunas University of Technology, Radvile˙nu˛ pl. 19, LT-50254 Kaunas, Lithuania
A R T I C L E I N F O
A B S T R A C T
Article history: Received 5 October 2015 Received in revised form 25 November 2015 Accepted 28 November 2015 Available online 3 December 2015
New derivatives of 5a,6-dihydro-12H-indolo[2,1-b][1,3]benzoxazine and 10 ,3,30 ,4-tetrahydrospiro[chromene-2,20 -indole] that possess trifluoromethyl groups on the indoline part of the molecule were synthesised, and their potential application for the detection of cyanide was evaluated. It was demonstrated that the new fluorinated chemosensors exhibited significantly shorter response times to cyanide detection compared with corresponding analogues bearing nitro groups. Structures of the newly synthesised compounds were assigned using standard 1H, 13C, 15N and 19F NMR spectroscopy techniques. ß 2015 Published by Elsevier B.V.
Keywords: Trifluoromethyl group 3H-indole Indolo[2,1-b][1,3]benzoxazine Spiro[chromene-2,20 -indole] Chemosensor Cyanide anion
1. Introduction The electron-withdrawing trifluoromethyl group (CF3) is considered to be an important structural motif in synthetic organic chemistry with applications in pharmaceuticals, agrochemicals and materials [1,2]. This group possesses unique steric and electronic properties, is resistant to metabolic oxidation and is often used as bioisosteres of methyl or chloride groups in the design of biologically active molecules [3,4]. Drugs such as the highly active antiretroviral therapy agent Sustiva, antidepressant Prozac, nonsteroidal anti-inflammatory agent Celebrex, pesticide Thiazopyr and the herbicide Fluazinam all possess trifluoromethyl moieties [5]. Recent examples on the beneficial effects of trifluoromethyl groups on target properties of functional materials include dyes for dye-sensitised solar cells [6,7], chelating agents [8], overcharge protection agents in lithium-ion batteries [9] and liquid crystals [10]. This work aims to synthesise trifluoromethyl group bearing indoline adducts with 2-chloromethyl-4-nitrophenol and to investigate their potential as molecular chemosensors for cyanide detection.
* Corresponding author at: Kaunas University of Technology, Department of Organic Chemistry, Radvilenu pl. 19, Kaunas, Lithuania. Tel.: +370 37451401; fax: +370 37451432. E-mail address: [email protected] (A. Sˇacˇkus). http://dx.doi.org/10.1016/j.jfluchem.2015.11.009 0022-1139/ß 2015 Published by Elsevier B.V.
Large amounts of cyanide are applied in a number of industrial processes every year, including gold extraction [11], electroplating [12] and nitrile synthesis [13]. However, the wide use of this highly toxic chemical has created a number of serious problems for the environment and human health [14]. Numerous methods have been developed to determine the presence of cyanide in food, drinking water, and the environment [15], but optical chemosensing of cyanides has been one of the most convenient and actively studied methods over the past decade [16,17]. For example, Ren et al. demonstrated that 2,8-dinitroindolo[2,1-b][1,3]benzoxazine (2, Scheme 1) obtained by the one step reaction of 2,3,3-trimethyl5-nitro-3H-indole (1) with 2-chloromethyl-4-nitrophenol and treatment with sodium cyanide yielded the stable adduct 3, which included a 4-nitrophenolate chromophore as a side chain that absorbed at approximately 410 nm [18]. This compound was commercialised by Sigma-Aldrich as a selective and sensitive optical chemosensor for the detection of cyanides [19]. Recently, we developed a new type of molecular chemosensor, including compound 4, that possesses a 10 ,3,30 ,4-tetrahydrospiro[chromene2,20 -indole] ring system [20,21]. These switches demonstrate a distinct colour change when treated with cyanide in acetonitrile solution buffered with sodium phosphate, and this procedure (e.g., leading to the formation of the adduct 5) is not significantly affected by other common anions. They exhibit high sensitivity to low concentrations of cyanide, meeting the water quality control
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Scheme 1. Cyanide receptors based on 2,3,3-trimethyl-5-nitro-3H-indole.
criterion of sensitivity below 0.05 mg/L, and show a very fast response. In this study, we developed methods to prepare compounds that possess analogous ring systems as 2 and 4 with trifluoromethyl groups at the indoline C-5 atom. In addition to the synthesis, we investigated the effects of these chemical modifications on their functional properties. 2. Results and discussion 2.1. Synthesis The synthetic strategy used to prepare the desired trifluoromethyl group possessing compounds is outlined in Scheme 2. The initial compound 5-trifluoromethyl-2,3,3-trimethyl-3H-indole (6) was obtained from 4-trifluoromethylphenylhydrazine and 2methylbutanone via a Fischer indole synthesis as described previously [22,23]. When compound 6 was treated with 2chloromethyl-4-nitrophenol (7) in acetonitrile, the reaction afforded 8-(trifluoromethyl)-5a,6-dihydro-12H-indolo[2,1-b][1,3] benzoxazine (8) as a white crystalline solid (Scheme 2). The synthesis of 50 -trifluoromethyl-10 ,3,30 ,4-tetrahydrospiro[chromene-2,20 -indoles] 11a–c first required the preparation of 1substituted 5-trifluoromethyl-3H-indolium salts 9a–c by alkylating compound 6 with methyl iodide, ethyl iodide and allyl bromide, respectively. Treatment of the salts 9a–c with a base afforded 5-trifluoromethyl-2-methylidene indolines 10a–c, which were used in subsequent reactions without further purification. The reaction of the heterocyclic enamines 10a–c with 2chloromethyl-4-nitrophenol (7) in acetonitrile resulted in alkylation at the b-carbon atom of the enamine moieties followed by
nucleophilic addition of the phenolic oxygen atom to the a-carbon atoms. This afforded the spiro compounds 11a–c, which were isolated from the reaction mixture by column chromatography. 2.2. NMR structural investigations The structures of the newly synthesised heterocyclic derivatives were investigated and confirmed by NMR spectroscopy using the combined application of standard NMR techniques such as COSY, DEPT, HSQC and HMBC, and 19F spectra. Characteristic signals in the 1H NMR spectrum of the chiral 8-(trifluoromethyl)-5a,6-dihydro-12H-indolo[2,1-b][1,3]benzoxazine (8), which possesses an asymmetric C-5a atom, were the slightly broadened singlets of the diastereotopic geminal methyl groups at C-6 at 1.21 and 1.56 ppm. The broadening of the aforementioned signals demonstrates that the equilibrated inversion of the chiral centre at C-5a and fast conversion between the corresponding R- and S-enantiomers takes part in solution, as previously shown with similar types of compounds [24,25]. The 13 C NMR spectrum of 8 contained a signal for C-5a at 102.7 ppm, which is covalently bonded with N- and O-atoms, while the corresponding carbon resonance of CF3 was located at 124.8 ppm with a relevant 1J(C,F) coupling constant of 270 Hz. In the 19F NMR spectrum, the CF3 group had a chemical shift at 64.14 ppm [26,27]. The full assignment of 1H, 13C, 15N and 19F chemical shifts for compound 8 is presented in Fig. 1A. The 1H NMR spectra of the chiral spiro compounds 11a–c contained the peaks of the geminal 30 ,30 -CH3 groups between 1.26 and 1.32 ppm, while the corresponding 13C NMR signal of the spiro-C-30 atom was present at ca. 104 ppm [28]. In the 19F NMR
Scheme 2. General synthesis of chemosensors (8, 11a–c) bearing trifluoromethyl substituents in the indoline part of the heterocyclic system.
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Fig. 1. 1H,
13
C (italics),
15
N (bold) and
19
F (bold) NMR chemical shifts (ppm) for 8 (A) and 11a (B) in CDCl3.
Table 1 Absorption maxima (lmax) and molar absorptivity (e) of compounds 8 and 11a–c in CH3CN/phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) without and with NaCN (10 equiv.). Entry
Compound
lmax (Without NaCN, nm)
e (Without NaCN, mM1/cm)
lmax (With NaCN, nm)
e (With NaCN, mM1/cm)
1
8
26.0 32.5
11a
3
11b
4
11c
52.4 19.8 15.6 17.8 33.8 12.6 11.4 35.8 15.8 13.4 33.2 13.4 11.5
287 414
2
205 252 296 (shldr) 315 205 257 320 205 260 321 206 258 321
265 296 422 269 (shldr) 298 422 295 422
12.1 10.0 19.0 11.4 19.6 21.0 17.8 16.9
spectra of compounds 11a–c, the trifluoromethyl groups exhibited typical chemical shifts that ranged from 63.77 to 63.84 ppm [26,27]. The corresponding carbon resonance of CF3 was located at ca. 125 ppm with a relevant 1J(C,F) coupling constant of 270 Hz. The full assignment of 1H, 13C and 19F chemical shifts of compound 11a is presented in Fig. 1B. When the NMR spectra of compounds 8 and 11a were taken in trifluoroacetic acid-d, the chemical shifts dramatically changed. For example, six protons of the geminal methyl groups became chemically equivalent to give one signal at ca. 1.80 ppm in a 1H NMR spectrum, which demonstrates the disappearance of molecular chirality. Meanwhile, the position of the indole moiety’s C-2 carbon signal shifted to 203 ppm and became similar to that of
Scheme 3. Cleavage of compounds 8 and 11a ring systems in trifluoroacetic acid solutions.
iodide 9a (199.4 ppm). Therefore, it can be concluded that when compounds 8 and 11a are treated with a strong protic acid, C–O bond cleavage results in heterocyclic system disintegration and formation of the corresponding 3H-indolium salts 12 and 13, respectively (Scheme 3). 2.3. Optical properties and chemosensing abilities towards cyanide Steady state absorbance spectra of compound 8 measured in CH3CN/phosphate buffer revealed only transitions in the UVregion of electronic spectra (Table 1, Fig. 2).
Fig. 2. Absorption spectra of 8 (0.1 mM, 298 K) in CH3CN/phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) without NaCN (spectrum A) and with NaCN (10 equiv, spectrum B).
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Scheme 4. Formation of 4-nitrophenolate chromophores.
The colourimetric cyanide sensing ability of compound 8 was monitored visually (by the naked eye) and by UV–vis spectroscopy methods. When a NaCN solution buffered with sodium phosphate was added to the aforementioned solution of 8, the colourless solution took on a yellow hue, and a new absorption band was observed in the visible area with lmax = 414 nm (Fig. 2, Table 1, entry 1). The appearance of this band in the visible region of an electronic spectrum can be rationalised by [1,3]oxazine ringopening and formation of a 4-nitrophenolate chromophore, resulting from the nucleophilic substitution of the phenolic oxygen by a cyanide group and formation of the adduct 14 (Scheme 4) [25]. The solutions of spiro compounds 11a–c did not have absorbance in the visible part of the electronic spectra, but they exhibited similar sensing behaviour when treated with cyanide. An absorption band was observed at lmax = 422 nm (Table 1, entries 2–4), which demonstrates the formation of adducts like indoline nitriles 15a–c that also possess a 4-nitrophenolate chromophore side chain [21,28]. One of the most important characteristics of optical chemosensors is their response time. The response time for absorbance changes upon addition of cyanide to the solutions of 8 and 11a–c in acetonitrile is presented in Figs. 3 and 4. After the addition of sodium cyanide to a solution of 8-trifluoromethyl benzoxazine 8, a strong absorption band appeared at 414 nm within 5 min; this process took up to 10 min for 8-nitrobenzoxazine 2 (Fig. 3). A similar investigation on the corresponding response times for compounds 11a–c showed that both electronic and steric effects
Fig. 3. Absorbance changes at 414 nm for 2 and 8 (0.1 mM, 298 K) in CH3CN/ phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) upon addition of NaCN (10 equiv).
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Fig. 4. Absorbance changes at 422 nm for 11a–c and 4 (0.1 mM, 298 K) in CH3CN/ phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) upon addition of NaCN (10 equiv).
could explain the influence of substituents at the indole nitrogen atom. Replacing nitro groups with trifluoromethyl groups on the core structure of this class of cyanide chemosensors speed up the appearance of a strong absorbance band in the visible part of the electronic spectrum (Fig. 4).
Fig. 5. Absorbance at 422 nm of 11a (0.1 mM, 298 K) in CH3CN/phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) in the presence of CN and other common anions (10 equiv), where A0 is the absorbance of 11a at 422 nm in the absence of CN.
Fig. 6. Absorbance at 414 nm of 8 (0.1 mM, 298 K) and at 422 nm of 11b (0.1 mM, 298 K) in a mixture of CH3CN/phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) in the presence of different concentration CN-, where A0 is the absorbance of 8 and 11b in the absence of CN (standard deviation 0.0002).
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To test the selectivity of the chemosensor 11a, parallel investigations were conducted using a series of other anions (F, Cl, Br, I, CH3COO, C2O42, HCO3, HSO3, HSO4, NO2, NO3, SCN, SO32, SO42, S2O32). The addition of excess amounts of these anions did not result in significant absorbance changes during UV–vis titration (Fig. 5), indicating that this chemosensor demonstrates excellent selectivity for cyanide over other common anions. To evaluate sensitivity, the calibration curves of cyanide concentration versus absorption at 414 nm for 8 and at 422 for 11b were built (Fig. 6), showing that these chemosensors are sensitive to low concentrations of CN and meet the recommended by WHO criterion for water quality, with sensitivity below 0.07 mg/L (27 107 M) [29]. 3. Conclusions In summary, derivatives of 5a,6-dihydro-12H-indolo[2,1b][1,3]benzoxazine and 10 ,3,30 ,4-tetrahydrospiro[chromene2,20 -indole] that possess trifluoromethyl groups on the indoline part of the molecule were synthesised using simple synthetic procedures from readily available 5-trifluoromethyl-2,3,3-trimethyl-3H-indole. These compounds exhibited significant colour changes when treated with cyanide in acetonitrile solutions buffered with sodium phosphate, which was measured colourimetrically or observed by the naked eye. Additionally, they exhibited high selectivity toward cyanide, and were not significantly affected by halides or other common anions. The displacement of nitro groups by trifluoromethyl groups on the indoline part of the core structure of the corresponding 5a,6dihydro-12H-indolo[2,1-b][1,3]benzoxazine and 10 ,3,30 ,4-tetrahydrospiro[chromene-2,20 -indole] derivatives enhanced the target properties of this classes of cyanide chemosensors and shortened the time required to detect the presence of cyanide anions at low concentrations. 4. Experimental 4.1. General Compound 6 was prepared according to previously reported procedures [22]. All other chemicals used in this study were commercially available. Analytical thin layer chromatography (TLC) was performed on aluminium foil backed plates (Merck Kieselgel 60 F254). Visualisation of the compounds was effected by UV light (254 nm) or by treatment with iodine vapour. Column chromatography was performed on silica gel SI 60 (43–60 mm, E. Merck). Melting points were determined in open capillary tubes with a Bu¨chi B-540 melting point apparatus and were uncorrected. Infrared spectra were recorded on a Perkin Elmer Spectrum One spectrometer using potassium bromide pellets. 1H NMR spectra were recorded at 400 MHz on a Bruker Avance III spectrometer with a 5 mm double resonance broad band BBO z-gradient room temperature probe, and at 700 MHz on a Bruker Avance III spectrometer equipped with a 5 mm TCI 1H–13C/15N/D z-gradient cryoprobe. 13C NMR spectra were collected using the same instruments at 100 and 175 MHz, respectively. The chemical shifts, expressed in ppm, were relative to tetramethylsilane (TMS). 15 N NMR spectra (71 MHz) were obtained on a Bruker Avance III spectrometer equipped with a 5 mm TCI 1H–13C/15N/D z-gradient cryoprobe and were referenced against neat, external nitromethane (coaxial capillary). 19F NMR spectra (376 MHz) were obtained on a Bruker Avance III instrument using C6F6 as an internal standard. Steady state absorption spectra of the solutions were measured using a Shimadzu scanning spectrophotometer model
UV-3101PC. High-resolution mass spectra (HRMS) were recorded in the ESI mode with a Bruker maXis spectrometer. 4.2. UV/vis absorption measurements For the measurement of UV/vis absorption compounds 8, 11a–c were dissolved in a mixture of CH3CN/phosphate buffer (Na2HPO4/ NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v, 298 K). Each solution (0.1 mM) was transferred into a spectrophotometer quartz cell (0.5 cm light path length) and 0.025 mL of 72 mM sodium cyanide solution in water was added. This volume was negligible compared to the initial volume of the solution in the cell (1.8 mL). The mixtures were shaken and the absorption was measured from 200 to 600 nm against a blank CH3CN/phosphate buffer (19:1, v/v, 298 K) sample. A 72 mM stock water solution of sodium cyanide was prepared from neat sodium cyanide. The anionic solutions for selectivity testing were prepared using sodium salts of various anions. Water was doubly distilled. To construct calibration curves of cyanide concentration versus the most sensitive absorption at 414 nm for 8, and at 422 nm for 11b, different cyanide solutions (75, 125, 250 mL of 0.72 mM and 25, 125, 250, 375, 500 mL of 3.6 mM) were added to 100 mL of 0.1 mM 8 solution and to 100 mL of 0.1 mM 11b solution in CH3CN/phosphate buffer. All of the added volumes of cyanide were negligible, with 0.75 mL as the highest volume, compared to the initial volume of the 8 and 11b solutions. 4.3. Synthesis 4.3.1. 5a,6,6-Trimethyl-2-nitro-8-(trifluoromethyl)-5a,6-dihydro12H-indolo[2,1-b][1,3]benzoxazine 8 To 2,3,3-Trimethyl-5-(trifluoromethyl)-3H-indole (6) (0.8 g, 3.5 mmol) dissolved in CH3CN (3 mL), 2-chloromethyl-4-nitrophenol (0.725 g, 3.87 mmol) was added and the mixture was stirred at reflux for 8 h. Then, the reaction mixture was allowed to reach room temperature and poured into water (40 mL). The separated product was extracted with Et2O (3 20 mL) and the combined organic extracts were dried over anhydrous Na2SO4, concentrated in vacuo. The obtained residue was subjected to flash chromatography on silica gel (hexane/acetone 9:1 v/v) to give the title compound 8 as a white crystalline solid (0.45 g, 34%); mp 182– 184 8C (from acetonitrile). IR (KBr), n (cm1): 3074 (C-arom), 2984 (C-alif), 1510 (NO2-asymm), 1345 (C–F), 1330 (NO2-symm), 1110 (C–F), 930, 812, 750, 639, 460. 1H NMR (700 MHz, CDCl3): d 1.21 (s, 3H, 6-CH3), 1.56 (s, 3H, 6-CH3), 1.60 (s, 3H, 5a-CH3), 4.66 (s, 2H, CH2), 6.61 (d, J = 8.0 Hz, 1H, 10-H), 6.75 (d, J = 9.1 Hz, 1H, 4-H), 7.32 (d, J = 2.8 Hz, 1H, 7-H), 7.36 (d, J = 8.0 Hz, 1H, 9-H), 7.97 (dd, J = 9.1, 2.8 Hz, 1H, 3-H), 8.08 (d, J = 2.8 Hz, 1H, 1-H). 13C NMR (175 MHz, CDCl3): d 16.5 (5a-CH3), 18.8 (6-CH3), 26.0 (6-CH3), 40.3 (CH2), 48.1 (C-6), 102.7 (C-5a), 108.0 (C-10), 118.5 (C-4), 118.6 (C–NO2), 119.6 (q, J = 10 Hz, C-7), 122.7 (q, J = 30 Hz, C-8), 123.4 (C-1), 124.3 (C-3), 124.8 (q, J = 270 Hz, CF3), 125.7 (q, J = 10 Hz, C-9), 138.8 (C), 140.9 (C), 149.7 (C), 158.8 (C). 15N NMR (71 MHz, CDCl3): d 297.3 (N11), 12.5 (NO2). 19F NMR (376 MHz, CDCl3): d 64.14 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C19H17F3N2O3Na+ 401.1083 [M + Na]+; found: 401.1087. NMR spectra of compound 8 in TFA-d (trifluoroacetate 12): 1H NMR (400 MHz, TFA-d): d 1.78 (s, 6H, 2 3-CH3), 3.13 (s, 3H, 2CH3), 5.87 (s, 2H, CH2), 7.16 (d, J = 9.0 Hz, 1H, 30 -H), 7.84 (d, J = 8.7 Hz, 1H, 7-H), 7.88 (dd, J = 8.7, 1.5 Hz, 1H, 6-H), 7.98 (d, J = 1.5 Hz, 1H, 4-H), 8.36 (dd, J = 9.0, 2.7 Hz, 1H, 40 -H), 8.62 (d, J = 2.7 Hz, 1H, 60 -H). 13C NMR (100 MHz, TFA-d): d 15.7 (2-CH3), 23.0 (2 3-CH3), 50.8 (CH2), 57.3 (C-3), 118.0 (C-6), 118.6 (C-30 ), 118.9 (C–NO2), 122.2 (q, J = 10 Hz, C-4), 124.7 (q, J = 270 Hz, CF3), 128.7–128.8 (m, C-60 , C-7), 129.7 (C-40 ), 135.2 (q, J = 30 Hz, C-5) 142.7 (C), 144.0 (C), 144.6 (C), 163.1 (C–OH), 203.3 (C-2).
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4.3.2. 1,2,3,3-Tetramethyl-5-(trifluoromethyl)-3H-indolium iodide 9a A mixture of compound 6 (1.0 g, 4.4 mmol) and iodomethane (1.25 g, 8.8 mmol) was stirred at rt for 24 h. The resulting crystalline material was isolated by filtration and recrystallised from EtOH to afford 9a as a reddish crystalline solid (0.68 g, 42%); mp 205–206 8C (decomp.); lit. mp 214–215 8C [22]. 1H NMR (400 MHz, Me2SO-d6): d 1.58 (s, 6H, 2 3-CH3), 2.83 (s, 3H, N–CH3), 4.01 (s, 3H, 2-CH3), 8.06 (d, J = 8.0 Hz, 1H, 6-H), 8.14 (d, J = 8.0 Hz, 1H, 7-H), 8.36 (s, 1H, 4-H). 13C NMR (100 MHz, Me2SO-d6): d 14.7 (CH3), 21.4 (2 CH3), 35.1 (CH3), 54.6 (C-3), 116.3 (C-7), 120.9 (d, J = 3.3 Hz, C-4), 124.0 (q, J = 270 Hz, CF3), 126.6 (d, J = 3.3 Hz, C-6), 129.5 (q, J = 30 Hz, C-5), 142.7 (C), 145.1 (C), 199.4 (C-2). 19F NMR (376 MHz, Me2SO-d6): d 62.86 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C13H15F3N+ 242.1151 [M I]+; found 242.1159. 4.3.3. 1-Ethyl-2,3,3-trimethyl-5-(trifluoromethyl)-3H-indolium iodide 9b A mixture of compound 6 (2.0 g, 8.8 mmol) with iodoethane (3.43 g, 22 mmol) was heated under reflux for 24 h. The resulting crystalline material was isolated by filtration and recrystallised from EtOH to afford 9b as a white crystalline solid (1.31 g, 39%); mp 198–199 8C. IR (KBr), n (cm1): 3119 (C-arom), 2979 (C-alif), 1623 (C5 5N+), 1326 (C–F), 1113 (C–F), 837, 730, 524. 1H NMR (400 MHz, Me2SO-d6): d 1.45 (t, J = 7.3 Hz, 3H, CH2CH3), 1.60 (s, 6H, 2 3CH3), 4.09 (s, 3H, 2-CH3), 4.55 (q, J = 7.3 Hz, 2H, CH2CH3), 8.04 (d, J = 8.5 Hz, 1H, 6-H), 8.23 (d, J = 8.5 Hz, 1H, 7-H), 8.38 (s, 1H, 4-H). 13 C NMR (100 MHz, Me2SO-d6): d 12.6 (CH2CH3), 14.6 (CH3), 21.6 (2 CH3), 43.6 (CH2CH3), 54.8 (C-3), 116.5 (C-7), 121.2 (d, J = 10 Hz, C-4), 123.9 (q, J = 270 Hz, CF3), 126.7 (d, J = 10 Hz, C-6), 129.6 (q, J = 30 Hz, C-5), 143.1, 143.8, 199.6 (C-2). 19F NMR (376 MHz, Me2SO-d6): d -62.92 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C14H17F3N+ 256.1308 [M I]+; found 256.1310. 4.3.4. 10 ,30 ,30 -Trimethyl-6-nitro-50 -(trifluoromethyl)-10 ,3,30 ,4tetrahydrospiro[chromene-2,20 -indole] 11a A stirred solution of iodide 9a (0.4 g, 1.08 mmol) in distilled water (20 mL) was treated with Na2CO3 (0.23 g, 2.16 mmol) at rt. The mixture became turbid immediately and was extracted with Et2O (3 15 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford crude intermediate enamine 10a as a brownish oil. This crude product was dissolved in CH3CN (3 mL), 2-chloromethyl-4-nitrophenol (0.2 g, 1.08 mmol) was added and the mixture was stirred under relux for 8 h. Then, the reaction mixture was allowed to reach room temperature and poured into water (40 mL). The separated product was extracted with Et2O (3 15 mL), combined extracts were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was subjected to flash chromatography on silica gel (hexane/acetone 9:1 v/v) to give the title compound 11a as a pale yellow crystalline solid (0.12 g, 32%); mp 154–155 8C (from acetonitrile). IR (KBr), n (cm1): 3075 (C-arom), 2972 (C-alif), 1513 (NO2-asymm), 1340 (C–F), 1327 (NO2-symm), 1112 (C–F), 967, 843, 638, 480. 1H NMR (400 MHz, CDCl3): d 1.26 (s, 6H, 2 30 CH3), 2.36–2.39 (m, 2H, CH2), 2.90 (s, 3H, N–CH3), 3.07–3.08 (m, 2H, CH2), 6.61 (d, J = 8.2 Hz, 1H, 70 -H), 6.79 (d, J = 9.0 Hz, 1H, 8-H), 7.24 (d, J = 1.8 Hz, 1H, 40 -H), 7.46 (ddd, J = 8.2, 1.8, 0.9 Hz, 1H, 60 -H), 8.00 (dd, J = 9.0, 2.8 Hz, 1H, 7-H), 8.05 (d, J = 2.8 Hz, 1H, 5-H). 13C NMR (100 MHz, CDCl3): d 21.8 (30 -CH3), 23.3 (CH2), 24.0 (CH2), 25.6 (30 CH3), 28.4 (N–CH3), 49.5 (C-30 ), 104.2 (C-spiro), 106.6 (C-70 ), 116.9 (C-8), 118.5 (q, J = 4 Hz, C-40 ), 121.1 (q, J = 30 Hz, C-50 ), 121.3 (C– NO2), 124.4 (C-7), 125.3 (C-5), 126.0 (q, J = 4 Hz, C-60 ), 125.1 (q, J = 270 Hz, CF3), 137.5 (C), 140.9 (C), 151.3 (C), 161.4 (C). 19F NMR (376 MHz, CDCl3): d 63.84 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C20H20F3N2O3+ 393.1421 [M + H]+; found 393.1423.
39
NMR spectra of compound 11a in TFA-d (trifluoroacetate 13): H NMR (400 MHz, TFA-d): d 1.83 (s, 6H, 2 3-CH3), 3.33–3.37 (m, 2H, CH2), 3.61–3.65 (m, 2H, CH2), 4.34 (s, 3H, N-CH3), 7.15 (d, J = 9.0 Hz, 1H, 30 -H), 7.93 (d, J = 8.5 Hz, 1H, 7-H), 8.02 (d, J = 1.5 Hz, 1H, 4-H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H, 6-H), 8.29 (dd, J = 9.0, 2.7 Hz, 1H, 40 -H), 8.36 (d, J = 2.7 Hz, 1H, 60 -H). 13C NMR (100 MHz, TFA-d): d 22.4 (2 3-CH3), 28.9 (CH2), 29.0 (CH2), 36.3 (N–CH3), 57.4 (C-3), 116.9 (C-7), 117.9 (C-30 ), 122.1 (q, J = 10 Hz, C-4), 124.6 (q, J = 270 Hz, C-5), 126.8 (C), 127.8 (C-40 ), 128.3 (C-60 ), 129.0 (q, J = 10 Hz, C-6), 135.8 (q, J = 270 Hz, CF3), 142.4 (C), 143.8 (C), 145.5 (C), 162.7 (C), 201.3 (C-2). 1
4.3.5. 10 -Ethyl-30 ,30 -dimethyl-6-nitro-50 -(trifluoromethyl)-10 ,3,30 ,4tetrahydrospiro[chromene-2,20 -indole] 11b Following the preparation of 11a, a solution of iodide 9b (1.0 g, 2.6 mmol) in distilled water (20 mL) was treated with Na2CO3 (0.55 g, 5.2 mmol) to afford the crude intermediate enamine 10b as a brownish oil. The crude product 10b was then treated with 2chloromethyl-4-nitro-phenol (0.4 g, 2.09 mmol) in acetonitrile (5 mL) and the workup gave the titled compound 11b as white crystals (0.32 g, 42%); mp 177–178 8C (from acetonitrile). IR (KBr), n (cm1): 3074 (C-arom), 2970 (C-alif), 1519 (NO2-asymm), 1337 (C–F), 1327 (NO2-symm), 1112 (C–F), 806, 748, 637, 485. 1H NMR (400 MHz, CDCl3): d 1.23 (t, J = 5.3 Hz, 3H, CH2CH3), 1.25 (s, 3H, 30 CH3), 1.27 (s, 3H, 30 -CH3), 2.28 (td, J = 14.0, 5.3 Hz, 1H, 1/2 CH2), 2.45 (ddd, J = 14.0, 5.3, 2.8 Hz, 1H, 1/2 CH2), 3.03 (ddd, J = 14.0, 5.3, 2.8 Hz, 1H, 1/2 CH2), 3.21–3.07 (m, 1H, 1/2 CH2), 3.30 (tt, J = 14.7, 7.1, 1H, 1/2 CH2CH3), 3.42 (dq, J = 14.7, 7.1, 1H, 1/2 CH2CH3), 6.59 (d, J = 8.5 Hz, 1H, 70 -H), 6.77 (d, J = 9.0 Hz, 1H, 8-H), 7.23 (d, J = 1.8 Hz, 1H, 40 -H), 7.44 (dd, J = 8.5, 1.8 Hz, 1H, 60 -H), 7.99 (dd, J = 9.0, 2.8 Hz, 1H, 7-H), 8.05 (d, J = 2.8 Hz, 1H, 5-H). 13C NMR (100 MHz, CDCl3): d 14.7 (CH3CH2), 21.8 (30 -CH3), 23.5 (CH2), 24.7 (CH2), 25.7 (30 -CH3), 37.4 (CH3CH2), 49.6 (C-30 ), 104.4 (C-spiro), 105.7 (C-70 ), 116.9 (C-8), 118.6 (q, J = 10 Hz, C-40 ), 120.7 (q, J = 30 Hz, C-50 ), 121.2 (C-NO2), 124.4 (C-7), 125.3 (C-5), 125.1 (q, J = 270 Hz, CF3), 126.1 (q, J = 10 Hz, C-60 ), 137.3 (C), 140.8 (C), 150.2 (C), 161.3 (C). 19F NMR (376 MHz, CDCl3): d 63.77 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C21H22F3N2O3+ 407.1577 [M + H]+; found 407.1580. 4.3.6. 10 -Allyl-30 ,30 -dimethyl-6-nitro-50 -(trifluoromethyl)-10 ,3,30 ,4tetrahydrospiro[chromene-2,20 -indole] 11c A mixture of compound 6 (2.0 g, 8.8 mmol) with allyl bromide (3.19 g, 26.4 mmol) was heated under reflux for 24 h. The resultant crystalline bromide 9c was isolated by filtration, washed with ethanol (2 mL), dried and dissolved in distilled water (20 mL). To this solution, Na2CO3 (0.51 g, 4.8 mmol) was added, the separated material was extracted with Et2O (3 15 mL), the combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford crude intermediate enamine 10c as a reddish oil. The obtained product was dissolved in CH3CN (5 mL), 2chloromethyl-4-nitrophenol (0.305 g, 1.625 mmol) was added and the mixture was stirred under reflux for 8 h. Standard workup of the reaction mixture and purification of the product by column chromatography gave the title compound 11c as white crystals (0.29 g, 46%); mp 152–153 8C (from acetonitrile). IR (KBr), n (cm1): 3058 (C-arom), 2973 (C-alif), 1524 (NO2-asymm), 1345 (C–F), 1328 (NO2-symm), 1115 (C–F), 965, 840, 750, 638, 482. 1H NMR (400 MHz, CDCl3): d 1.28 (s, 3H, 30 -CH3), 1.32 (s, 3H, 30 -CH3), 2.21 (td, J = 14.0, 5.3 Hz, 1H, 1/2 CH2), 2.46 (ddd, J = 14.0, 5.3, 2.8 Hz, 1H, 1/2 CH2), 3.01 (ddd, J = 17.0, 5.3, 2.8 Hz, 1H, 1/2 CH2), 3.13 (ddd, J = 18.1, 13.3, 5.3 Hz, 1H, 1/2 CH2), 3.80 (ddt, J = 18.1, 4.2, 1.9 Hz, 1H, 1/2 N–CH2), 4.00 (ddt, J = 18.1, 4.2, 1.9 Hz, 1H, 1/2 N– CH2), 5.17 (dq, J = 10.3, 1.8 Hz, 1H, 1/2 CH2CH5 5CH2), 5.25 (dq, J = 17.1, 1.8 Hz, 1H, 1/2 CH2CH5 5CH2), 5.91 (ddt, J = 17.1, 10.3 4.5 Hz, 1H, CH2CH5 5CH2), 6.56 (d, J = 8.5 Hz, 1H, 70 -H), 6.78
40
G. Ragaite˙ et al. / Journal of Fluorine Chemistry 182 (2016) 34–40
(d, J = 9.0 Hz, 1H, 8-H), 7.24–7.26 (m, 1H, 40 -H), 7.40–7.45 (m, 1H, 60 -H), 8.00 (dd, J = 9.0, 2.8 Hz, 1H, 7-H), 8.04 (d, J = 2.8 Hz, 1H, 5-H). 13 C NMR (100 MHz, CDCl3): d 21.9 (30 -CH3), 23.3 (CH2), 24.7 (CH2), 26.1 (30 -CH3), 45.4 (N-CH2), 49.6 (C-30 ), 104.3 (C-spiro), 106.6 (C-70 ), 115.8 (CH2CH5 5CH2), 116.9 (C-8), 118.6 (q, J = 10 Hz, C-40 ), 121.1 (C–NO2), 121.2 (q, J = 30 Hz, C-50 ), 124.3 (C-7), 125.1 (q, J = 270 Hz, CF3), 125.3 (C-5), 126.0 (q, J = 10 Hz, C-60 ), 134.2 (CH2CH5 5CH2), 137.3 (C), 140.9 (C), 150.5 (C), 161.2 (C). 19F NMR (376 MHz, CDCl3): d 63.84 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C22H22F3N2O3+ 419.1577 [M + H]+; found 419.1576. Acknowledgements This research was funded by a grant (No. MIP-022/2013) from the Research Council of Lithuania.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2015. 11.009. References [1] V.P. Reddy, Organofluorine Compounds in Biology and Medicine, Elsevier, Amsterdam, Oxford, Waltham, 2015. [2] I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley, Chichester, 2009. [3] C.G. Wermuth, Molecular variations based on isosteric replacements, in: C.G. Wermuth (Ed.), The Practice of Medicinal Chemistry, second ed., Academic Press, Amsterdam, Boston, Heidelberg, London, New York, Oxford, Paris, San Diego, San Francisco, Singapore, Tokyo, 2003, pp. 189–214. [4] J. Elguero, G.I. Yranzo, J. Laynez, P. Jimenez, M. Menendez, J. Catalan, J.L.G. De Paz, F. Anvia, R.W. Taft, J. Org. Chem. 56 (1991) 3942–3947. [5] M. Quirmbach, H. Steiner, Chim. Oggi 27 (2009) 23–26.
[6] F. Brunner, Y.M. Klein, S. Keller, C.D. Morris, A. Prescimone, E.C. Constable, C.E. Housecroft, RSC Adv. 5 (2015) 58694–58703. [7] J. Hong, H. Lai, Y. Liu, C. Yuan, Y. Li, P. Liuand, Q. Fang, RSC Adv. 3 (2013) 1069–1072. [8] A. Abdullah, C.J. Roxburgh, P.G. Sammes, Dyes Pigm. 76 (2008) 319–326. [9] A.P. Kaur, S. Ergun, C.F. Elliott, S.A. Odom, J. Mater. Chem. A 2 (2014) 18190–18193. [10] Y.M. Zhang, Y.W. Wang, M. Zhang, J.F. Liu, J. Si, D.D. Dang, Adv. Mater. Res. 785–786 (2013) 690–692. [11] P. Karimi, H. Abdollahi, A. Amini, M. Noaparast, S.Z. Shafaei, F. Habashi, Int. J. Miner. Process. 95 (2010) 68–77. [12] N. Kanani, Electroplating: Basic Principles, Processes and Practice, Elsevier, Amsterdam, 2004. [13] Y.Q. Cao, B.H. Chen, B.G. Pei, Synth. Commun. 31 (2001) 2203–2207. [14] D.A. Dzombak, R.S. Ghosh (Eds.), Cyanide in Water and Soil: Chemistry, Risk, and Management, CRC Press, Boca Raton, FL, 2006. [15] B. Wang, E.V. Anslyn (Eds.), Chemosensors: Principles, Strategies, and Applications, John Wiley& Sons, Hoboken, NJ, 2011. [16] Z. Xu, X. Chen, H.N. Kim, J. Yoon, J. Chem. Soc. Rev. 39 (2010) 127–137. [17] Z. Xu, X. Chen, H.N. Kim, J. Yoon, Chem. Soc. Rev. 43 (2014) 4312–4324. [18] J. Ren, W. Zhu, H. Tian, Talanta 75 (2008) 760–764. [19] M. Jeitziner, New Spectroscopic reagents for UV/VIS by Sigma-Aldrich, Custom Solutions for Analytical Applications, Analytix, vol. 4, Sigma-Aldrich Chemie GmbH, Switzerland, 2009, p. 10Available via hwww.sigma-aldrich.com/ analytixi. [20] A. Sˇacˇkus, V. Martynaitis, M. Dagiliene, S. Kriksˇtolaityte˙, G. Ragaite˙, WIPO Patent WO/2014/189348 A1. [21] M. Dagiliene˙, V. Martynaitis, V. Krisˇcˇiu¯niene˙, S. Kriksˇtolaityte˙, A. Sˇacˇkus, ChemistryOpen 4 (2015) 363–369. [22] V.I. Troitskaya, I.G. Oksengendler, S.V. Pazenok, M.S. Lyubich, S.M. Larina, L.M. Yagupol’skii, Chem. Heterocycl. Compd. 18 (1982) 39–43. [23] D. Oushiki, H. Kojima, Y. Takahashi, T. Komatsu, T. Terai, K. Hanaoka, M. Nishikawa, Y. Takakura, T. Nagano, Anal. Chem. 84 (2012) 4404–4410. [24] A.A. Shachkus, J.A. Degutis, A.H. Urbonavichius, Chem. Heterocycl. Compd. 25 (1989) 562–565. [25] M. Tomasulo, S. Sortino, A.J.P. White, F.M. Raymo, J. Org. Chem. 70 (2005) 8180–8189. [26] B. Palka, A. Di Capua, M. Anzini, G. Vilkauskaite˙, A. Sˇacˇkus, W. Holzer, Beilstein J. Org. Chem. 10 (2014) 1759–1764. [27] B. Raimer, P.G. Jones, T. Lindel, J. Fluorine Chem. 166 (2014) 8–14. [28] M. Dagiliene˙, A. Sˇacˇkus, M. Vengris, K. Redeckas, V. Voiciuk, W. Holzer, A. Sˇacˇkus, Tetrahedron 69 (2013) 9309–9315. [29] WHO, third ed., World Health Organization Guidelines for Drinking-water Quality, vol. 1, WHO, Geneva, 2008.
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
Synthesis of trifluoromethyl group bearing indoline-based heterocyclic systems and their application for the detection of cyanide Greta Ragaite˙ a, Migle˙ Dagiliene˙ a, Sonata Kriksˇtolaityte˙ b, Vytas Martynaitis b, Algirdas Sˇacˇkus a,b,* a b
Institute of Synthetic Chemistry, Kaunas University of Technology, Radvile˙nu˛ pl. 19, LT-50254 Kaunas, Lithuania Department of Organic Chemistry, Kaunas University of Technology, Radvile˙nu˛ pl. 19, LT-50254 Kaunas, Lithuania
A R T I C L E I N F O
A B S T R A C T
Article history: Received 5 October 2015 Received in revised form 25 November 2015 Accepted 28 November 2015 Available online 3 December 2015
New derivatives of 5a,6-dihydro-12H-indolo[2,1-b][1,3]benzoxazine and 10 ,3,30 ,4-tetrahydrospiro[chromene-2,20 -indole] that possess trifluoromethyl groups on the indoline part of the molecule were synthesised, and their potential application for the detection of cyanide was evaluated. It was demonstrated that the new fluorinated chemosensors exhibited significantly shorter response times to cyanide detection compared with corresponding analogues bearing nitro groups. Structures of the newly synthesised compounds were assigned using standard 1H, 13C, 15N and 19F NMR spectroscopy techniques. ß 2015 Published by Elsevier B.V.
Keywords: Trifluoromethyl group 3H-indole Indolo[2,1-b][1,3]benzoxazine Spiro[chromene-2,20 -indole] Chemosensor Cyanide anion
1. Introduction The electron-withdrawing trifluoromethyl group (CF3) is considered to be an important structural motif in synthetic organic chemistry with applications in pharmaceuticals, agrochemicals and materials [1,2]. This group possesses unique steric and electronic properties, is resistant to metabolic oxidation and is often used as bioisosteres of methyl or chloride groups in the design of biologically active molecules [3,4]. Drugs such as the highly active antiretroviral therapy agent Sustiva, antidepressant Prozac, nonsteroidal anti-inflammatory agent Celebrex, pesticide Thiazopyr and the herbicide Fluazinam all possess trifluoromethyl moieties [5]. Recent examples on the beneficial effects of trifluoromethyl groups on target properties of functional materials include dyes for dye-sensitised solar cells [6,7], chelating agents [8], overcharge protection agents in lithium-ion batteries [9] and liquid crystals [10]. This work aims to synthesise trifluoromethyl group bearing indoline adducts with 2-chloromethyl-4-nitrophenol and to investigate their potential as molecular chemosensors for cyanide detection.
* Corresponding author at: Kaunas University of Technology, Department of Organic Chemistry, Radvilenu pl. 19, Kaunas, Lithuania. Tel.: +370 37451401; fax: +370 37451432. E-mail address: [email protected] (A. Sˇacˇkus). http://dx.doi.org/10.1016/j.jfluchem.2015.11.009 0022-1139/ß 2015 Published by Elsevier B.V.
Large amounts of cyanide are applied in a number of industrial processes every year, including gold extraction [11], electroplating [12] and nitrile synthesis [13]. However, the wide use of this highly toxic chemical has created a number of serious problems for the environment and human health [14]. Numerous methods have been developed to determine the presence of cyanide in food, drinking water, and the environment [15], but optical chemosensing of cyanides has been one of the most convenient and actively studied methods over the past decade [16,17]. For example, Ren et al. demonstrated that 2,8-dinitroindolo[2,1-b][1,3]benzoxazine (2, Scheme 1) obtained by the one step reaction of 2,3,3-trimethyl5-nitro-3H-indole (1) with 2-chloromethyl-4-nitrophenol and treatment with sodium cyanide yielded the stable adduct 3, which included a 4-nitrophenolate chromophore as a side chain that absorbed at approximately 410 nm [18]. This compound was commercialised by Sigma-Aldrich as a selective and sensitive optical chemosensor for the detection of cyanides [19]. Recently, we developed a new type of molecular chemosensor, including compound 4, that possesses a 10 ,3,30 ,4-tetrahydrospiro[chromene2,20 -indole] ring system [20,21]. These switches demonstrate a distinct colour change when treated with cyanide in acetonitrile solution buffered with sodium phosphate, and this procedure (e.g., leading to the formation of the adduct 5) is not significantly affected by other common anions. They exhibit high sensitivity to low concentrations of cyanide, meeting the water quality control
G. Ragaite˙ et al. / Journal of Fluorine Chemistry 182 (2016) 34–40
35
Scheme 1. Cyanide receptors based on 2,3,3-trimethyl-5-nitro-3H-indole.
criterion of sensitivity below 0.05 mg/L, and show a very fast response. In this study, we developed methods to prepare compounds that possess analogous ring systems as 2 and 4 with trifluoromethyl groups at the indoline C-5 atom. In addition to the synthesis, we investigated the effects of these chemical modifications on their functional properties. 2. Results and discussion 2.1. Synthesis The synthetic strategy used to prepare the desired trifluoromethyl group possessing compounds is outlined in Scheme 2. The initial compound 5-trifluoromethyl-2,3,3-trimethyl-3H-indole (6) was obtained from 4-trifluoromethylphenylhydrazine and 2methylbutanone via a Fischer indole synthesis as described previously [22,23]. When compound 6 was treated with 2chloromethyl-4-nitrophenol (7) in acetonitrile, the reaction afforded 8-(trifluoromethyl)-5a,6-dihydro-12H-indolo[2,1-b][1,3] benzoxazine (8) as a white crystalline solid (Scheme 2). The synthesis of 50 -trifluoromethyl-10 ,3,30 ,4-tetrahydrospiro[chromene-2,20 -indoles] 11a–c first required the preparation of 1substituted 5-trifluoromethyl-3H-indolium salts 9a–c by alkylating compound 6 with methyl iodide, ethyl iodide and allyl bromide, respectively. Treatment of the salts 9a–c with a base afforded 5-trifluoromethyl-2-methylidene indolines 10a–c, which were used in subsequent reactions without further purification. The reaction of the heterocyclic enamines 10a–c with 2chloromethyl-4-nitrophenol (7) in acetonitrile resulted in alkylation at the b-carbon atom of the enamine moieties followed by
nucleophilic addition of the phenolic oxygen atom to the a-carbon atoms. This afforded the spiro compounds 11a–c, which were isolated from the reaction mixture by column chromatography. 2.2. NMR structural investigations The structures of the newly synthesised heterocyclic derivatives were investigated and confirmed by NMR spectroscopy using the combined application of standard NMR techniques such as COSY, DEPT, HSQC and HMBC, and 19F spectra. Characteristic signals in the 1H NMR spectrum of the chiral 8-(trifluoromethyl)-5a,6-dihydro-12H-indolo[2,1-b][1,3]benzoxazine (8), which possesses an asymmetric C-5a atom, were the slightly broadened singlets of the diastereotopic geminal methyl groups at C-6 at 1.21 and 1.56 ppm. The broadening of the aforementioned signals demonstrates that the equilibrated inversion of the chiral centre at C-5a and fast conversion between the corresponding R- and S-enantiomers takes part in solution, as previously shown with similar types of compounds [24,25]. The 13 C NMR spectrum of 8 contained a signal for C-5a at 102.7 ppm, which is covalently bonded with N- and O-atoms, while the corresponding carbon resonance of CF3 was located at 124.8 ppm with a relevant 1J(C,F) coupling constant of 270 Hz. In the 19F NMR spectrum, the CF3 group had a chemical shift at 64.14 ppm [26,27]. The full assignment of 1H, 13C, 15N and 19F chemical shifts for compound 8 is presented in Fig. 1A. The 1H NMR spectra of the chiral spiro compounds 11a–c contained the peaks of the geminal 30 ,30 -CH3 groups between 1.26 and 1.32 ppm, while the corresponding 13C NMR signal of the spiro-C-30 atom was present at ca. 104 ppm [28]. In the 19F NMR
Scheme 2. General synthesis of chemosensors (8, 11a–c) bearing trifluoromethyl substituents in the indoline part of the heterocyclic system.
G. Ragaite˙ et al. / Journal of Fluorine Chemistry 182 (2016) 34–40
36
Fig. 1. 1H,
13
C (italics),
15
N (bold) and
19
F (bold) NMR chemical shifts (ppm) for 8 (A) and 11a (B) in CDCl3.
Table 1 Absorption maxima (lmax) and molar absorptivity (e) of compounds 8 and 11a–c in CH3CN/phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) without and with NaCN (10 equiv.). Entry
Compound
lmax (Without NaCN, nm)
e (Without NaCN, mM1/cm)
lmax (With NaCN, nm)
e (With NaCN, mM1/cm)
1
8
26.0 32.5
11a
3
11b
4
11c
52.4 19.8 15.6 17.8 33.8 12.6 11.4 35.8 15.8 13.4 33.2 13.4 11.5
287 414
2
205 252 296 (shldr) 315 205 257 320 205 260 321 206 258 321
265 296 422 269 (shldr) 298 422 295 422
12.1 10.0 19.0 11.4 19.6 21.0 17.8 16.9
spectra of compounds 11a–c, the trifluoromethyl groups exhibited typical chemical shifts that ranged from 63.77 to 63.84 ppm [26,27]. The corresponding carbon resonance of CF3 was located at ca. 125 ppm with a relevant 1J(C,F) coupling constant of 270 Hz. The full assignment of 1H, 13C and 19F chemical shifts of compound 11a is presented in Fig. 1B. When the NMR spectra of compounds 8 and 11a were taken in trifluoroacetic acid-d, the chemical shifts dramatically changed. For example, six protons of the geminal methyl groups became chemically equivalent to give one signal at ca. 1.80 ppm in a 1H NMR spectrum, which demonstrates the disappearance of molecular chirality. Meanwhile, the position of the indole moiety’s C-2 carbon signal shifted to 203 ppm and became similar to that of
Scheme 3. Cleavage of compounds 8 and 11a ring systems in trifluoroacetic acid solutions.
iodide 9a (199.4 ppm). Therefore, it can be concluded that when compounds 8 and 11a are treated with a strong protic acid, C–O bond cleavage results in heterocyclic system disintegration and formation of the corresponding 3H-indolium salts 12 and 13, respectively (Scheme 3). 2.3. Optical properties and chemosensing abilities towards cyanide Steady state absorbance spectra of compound 8 measured in CH3CN/phosphate buffer revealed only transitions in the UVregion of electronic spectra (Table 1, Fig. 2).
Fig. 2. Absorption spectra of 8 (0.1 mM, 298 K) in CH3CN/phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) without NaCN (spectrum A) and with NaCN (10 equiv, spectrum B).
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Scheme 4. Formation of 4-nitrophenolate chromophores.
The colourimetric cyanide sensing ability of compound 8 was monitored visually (by the naked eye) and by UV–vis spectroscopy methods. When a NaCN solution buffered with sodium phosphate was added to the aforementioned solution of 8, the colourless solution took on a yellow hue, and a new absorption band was observed in the visible area with lmax = 414 nm (Fig. 2, Table 1, entry 1). The appearance of this band in the visible region of an electronic spectrum can be rationalised by [1,3]oxazine ringopening and formation of a 4-nitrophenolate chromophore, resulting from the nucleophilic substitution of the phenolic oxygen by a cyanide group and formation of the adduct 14 (Scheme 4) [25]. The solutions of spiro compounds 11a–c did not have absorbance in the visible part of the electronic spectra, but they exhibited similar sensing behaviour when treated with cyanide. An absorption band was observed at lmax = 422 nm (Table 1, entries 2–4), which demonstrates the formation of adducts like indoline nitriles 15a–c that also possess a 4-nitrophenolate chromophore side chain [21,28]. One of the most important characteristics of optical chemosensors is their response time. The response time for absorbance changes upon addition of cyanide to the solutions of 8 and 11a–c in acetonitrile is presented in Figs. 3 and 4. After the addition of sodium cyanide to a solution of 8-trifluoromethyl benzoxazine 8, a strong absorption band appeared at 414 nm within 5 min; this process took up to 10 min for 8-nitrobenzoxazine 2 (Fig. 3). A similar investigation on the corresponding response times for compounds 11a–c showed that both electronic and steric effects
Fig. 3. Absorbance changes at 414 nm for 2 and 8 (0.1 mM, 298 K) in CH3CN/ phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) upon addition of NaCN (10 equiv).
37
Fig. 4. Absorbance changes at 422 nm for 11a–c and 4 (0.1 mM, 298 K) in CH3CN/ phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) upon addition of NaCN (10 equiv).
could explain the influence of substituents at the indole nitrogen atom. Replacing nitro groups with trifluoromethyl groups on the core structure of this class of cyanide chemosensors speed up the appearance of a strong absorbance band in the visible part of the electronic spectrum (Fig. 4).
Fig. 5. Absorbance at 422 nm of 11a (0.1 mM, 298 K) in CH3CN/phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) in the presence of CN and other common anions (10 equiv), where A0 is the absorbance of 11a at 422 nm in the absence of CN.
Fig. 6. Absorbance at 414 nm of 8 (0.1 mM, 298 K) and at 422 nm of 11b (0.1 mM, 298 K) in a mixture of CH3CN/phosphate buffer (Na2HPO4/NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v) in the presence of different concentration CN-, where A0 is the absorbance of 8 and 11b in the absence of CN (standard deviation 0.0002).
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To test the selectivity of the chemosensor 11a, parallel investigations were conducted using a series of other anions (F, Cl, Br, I, CH3COO, C2O42, HCO3, HSO3, HSO4, NO2, NO3, SCN, SO32, SO42, S2O32). The addition of excess amounts of these anions did not result in significant absorbance changes during UV–vis titration (Fig. 5), indicating that this chemosensor demonstrates excellent selectivity for cyanide over other common anions. To evaluate sensitivity, the calibration curves of cyanide concentration versus absorption at 414 nm for 8 and at 422 for 11b were built (Fig. 6), showing that these chemosensors are sensitive to low concentrations of CN and meet the recommended by WHO criterion for water quality, with sensitivity below 0.07 mg/L (27 107 M) [29]. 3. Conclusions In summary, derivatives of 5a,6-dihydro-12H-indolo[2,1b][1,3]benzoxazine and 10 ,3,30 ,4-tetrahydrospiro[chromene2,20 -indole] that possess trifluoromethyl groups on the indoline part of the molecule were synthesised using simple synthetic procedures from readily available 5-trifluoromethyl-2,3,3-trimethyl-3H-indole. These compounds exhibited significant colour changes when treated with cyanide in acetonitrile solutions buffered with sodium phosphate, which was measured colourimetrically or observed by the naked eye. Additionally, they exhibited high selectivity toward cyanide, and were not significantly affected by halides or other common anions. The displacement of nitro groups by trifluoromethyl groups on the indoline part of the core structure of the corresponding 5a,6dihydro-12H-indolo[2,1-b][1,3]benzoxazine and 10 ,3,30 ,4-tetrahydrospiro[chromene-2,20 -indole] derivatives enhanced the target properties of this classes of cyanide chemosensors and shortened the time required to detect the presence of cyanide anions at low concentrations. 4. Experimental 4.1. General Compound 6 was prepared according to previously reported procedures [22]. All other chemicals used in this study were commercially available. Analytical thin layer chromatography (TLC) was performed on aluminium foil backed plates (Merck Kieselgel 60 F254). Visualisation of the compounds was effected by UV light (254 nm) or by treatment with iodine vapour. Column chromatography was performed on silica gel SI 60 (43–60 mm, E. Merck). Melting points were determined in open capillary tubes with a Bu¨chi B-540 melting point apparatus and were uncorrected. Infrared spectra were recorded on a Perkin Elmer Spectrum One spectrometer using potassium bromide pellets. 1H NMR spectra were recorded at 400 MHz on a Bruker Avance III spectrometer with a 5 mm double resonance broad band BBO z-gradient room temperature probe, and at 700 MHz on a Bruker Avance III spectrometer equipped with a 5 mm TCI 1H–13C/15N/D z-gradient cryoprobe. 13C NMR spectra were collected using the same instruments at 100 and 175 MHz, respectively. The chemical shifts, expressed in ppm, were relative to tetramethylsilane (TMS). 15 N NMR spectra (71 MHz) were obtained on a Bruker Avance III spectrometer equipped with a 5 mm TCI 1H–13C/15N/D z-gradient cryoprobe and were referenced against neat, external nitromethane (coaxial capillary). 19F NMR spectra (376 MHz) were obtained on a Bruker Avance III instrument using C6F6 as an internal standard. Steady state absorption spectra of the solutions were measured using a Shimadzu scanning spectrophotometer model
UV-3101PC. High-resolution mass spectra (HRMS) were recorded in the ESI mode with a Bruker maXis spectrometer. 4.2. UV/vis absorption measurements For the measurement of UV/vis absorption compounds 8, 11a–c were dissolved in a mixture of CH3CN/phosphate buffer (Na2HPO4/ NaH2PO4, 7.5 mM, pH 7.6) (19:1, v/v, 298 K). Each solution (0.1 mM) was transferred into a spectrophotometer quartz cell (0.5 cm light path length) and 0.025 mL of 72 mM sodium cyanide solution in water was added. This volume was negligible compared to the initial volume of the solution in the cell (1.8 mL). The mixtures were shaken and the absorption was measured from 200 to 600 nm against a blank CH3CN/phosphate buffer (19:1, v/v, 298 K) sample. A 72 mM stock water solution of sodium cyanide was prepared from neat sodium cyanide. The anionic solutions for selectivity testing were prepared using sodium salts of various anions. Water was doubly distilled. To construct calibration curves of cyanide concentration versus the most sensitive absorption at 414 nm for 8, and at 422 nm for 11b, different cyanide solutions (75, 125, 250 mL of 0.72 mM and 25, 125, 250, 375, 500 mL of 3.6 mM) were added to 100 mL of 0.1 mM 8 solution and to 100 mL of 0.1 mM 11b solution in CH3CN/phosphate buffer. All of the added volumes of cyanide were negligible, with 0.75 mL as the highest volume, compared to the initial volume of the 8 and 11b solutions. 4.3. Synthesis 4.3.1. 5a,6,6-Trimethyl-2-nitro-8-(trifluoromethyl)-5a,6-dihydro12H-indolo[2,1-b][1,3]benzoxazine 8 To 2,3,3-Trimethyl-5-(trifluoromethyl)-3H-indole (6) (0.8 g, 3.5 mmol) dissolved in CH3CN (3 mL), 2-chloromethyl-4-nitrophenol (0.725 g, 3.87 mmol) was added and the mixture was stirred at reflux for 8 h. Then, the reaction mixture was allowed to reach room temperature and poured into water (40 mL). The separated product was extracted with Et2O (3 20 mL) and the combined organic extracts were dried over anhydrous Na2SO4, concentrated in vacuo. The obtained residue was subjected to flash chromatography on silica gel (hexane/acetone 9:1 v/v) to give the title compound 8 as a white crystalline solid (0.45 g, 34%); mp 182– 184 8C (from acetonitrile). IR (KBr), n (cm1): 3074 (C-arom), 2984 (C-alif), 1510 (NO2-asymm), 1345 (C–F), 1330 (NO2-symm), 1110 (C–F), 930, 812, 750, 639, 460. 1H NMR (700 MHz, CDCl3): d 1.21 (s, 3H, 6-CH3), 1.56 (s, 3H, 6-CH3), 1.60 (s, 3H, 5a-CH3), 4.66 (s, 2H, CH2), 6.61 (d, J = 8.0 Hz, 1H, 10-H), 6.75 (d, J = 9.1 Hz, 1H, 4-H), 7.32 (d, J = 2.8 Hz, 1H, 7-H), 7.36 (d, J = 8.0 Hz, 1H, 9-H), 7.97 (dd, J = 9.1, 2.8 Hz, 1H, 3-H), 8.08 (d, J = 2.8 Hz, 1H, 1-H). 13C NMR (175 MHz, CDCl3): d 16.5 (5a-CH3), 18.8 (6-CH3), 26.0 (6-CH3), 40.3 (CH2), 48.1 (C-6), 102.7 (C-5a), 108.0 (C-10), 118.5 (C-4), 118.6 (C–NO2), 119.6 (q, J = 10 Hz, C-7), 122.7 (q, J = 30 Hz, C-8), 123.4 (C-1), 124.3 (C-3), 124.8 (q, J = 270 Hz, CF3), 125.7 (q, J = 10 Hz, C-9), 138.8 (C), 140.9 (C), 149.7 (C), 158.8 (C). 15N NMR (71 MHz, CDCl3): d 297.3 (N11), 12.5 (NO2). 19F NMR (376 MHz, CDCl3): d 64.14 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C19H17F3N2O3Na+ 401.1083 [M + Na]+; found: 401.1087. NMR spectra of compound 8 in TFA-d (trifluoroacetate 12): 1H NMR (400 MHz, TFA-d): d 1.78 (s, 6H, 2 3-CH3), 3.13 (s, 3H, 2CH3), 5.87 (s, 2H, CH2), 7.16 (d, J = 9.0 Hz, 1H, 30 -H), 7.84 (d, J = 8.7 Hz, 1H, 7-H), 7.88 (dd, J = 8.7, 1.5 Hz, 1H, 6-H), 7.98 (d, J = 1.5 Hz, 1H, 4-H), 8.36 (dd, J = 9.0, 2.7 Hz, 1H, 40 -H), 8.62 (d, J = 2.7 Hz, 1H, 60 -H). 13C NMR (100 MHz, TFA-d): d 15.7 (2-CH3), 23.0 (2 3-CH3), 50.8 (CH2), 57.3 (C-3), 118.0 (C-6), 118.6 (C-30 ), 118.9 (C–NO2), 122.2 (q, J = 10 Hz, C-4), 124.7 (q, J = 270 Hz, CF3), 128.7–128.8 (m, C-60 , C-7), 129.7 (C-40 ), 135.2 (q, J = 30 Hz, C-5) 142.7 (C), 144.0 (C), 144.6 (C), 163.1 (C–OH), 203.3 (C-2).
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4.3.2. 1,2,3,3-Tetramethyl-5-(trifluoromethyl)-3H-indolium iodide 9a A mixture of compound 6 (1.0 g, 4.4 mmol) and iodomethane (1.25 g, 8.8 mmol) was stirred at rt for 24 h. The resulting crystalline material was isolated by filtration and recrystallised from EtOH to afford 9a as a reddish crystalline solid (0.68 g, 42%); mp 205–206 8C (decomp.); lit. mp 214–215 8C [22]. 1H NMR (400 MHz, Me2SO-d6): d 1.58 (s, 6H, 2 3-CH3), 2.83 (s, 3H, N–CH3), 4.01 (s, 3H, 2-CH3), 8.06 (d, J = 8.0 Hz, 1H, 6-H), 8.14 (d, J = 8.0 Hz, 1H, 7-H), 8.36 (s, 1H, 4-H). 13C NMR (100 MHz, Me2SO-d6): d 14.7 (CH3), 21.4 (2 CH3), 35.1 (CH3), 54.6 (C-3), 116.3 (C-7), 120.9 (d, J = 3.3 Hz, C-4), 124.0 (q, J = 270 Hz, CF3), 126.6 (d, J = 3.3 Hz, C-6), 129.5 (q, J = 30 Hz, C-5), 142.7 (C), 145.1 (C), 199.4 (C-2). 19F NMR (376 MHz, Me2SO-d6): d 62.86 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C13H15F3N+ 242.1151 [M I]+; found 242.1159. 4.3.3. 1-Ethyl-2,3,3-trimethyl-5-(trifluoromethyl)-3H-indolium iodide 9b A mixture of compound 6 (2.0 g, 8.8 mmol) with iodoethane (3.43 g, 22 mmol) was heated under reflux for 24 h. The resulting crystalline material was isolated by filtration and recrystallised from EtOH to afford 9b as a white crystalline solid (1.31 g, 39%); mp 198–199 8C. IR (KBr), n (cm1): 3119 (C-arom), 2979 (C-alif), 1623 (C5 5N+), 1326 (C–F), 1113 (C–F), 837, 730, 524. 1H NMR (400 MHz, Me2SO-d6): d 1.45 (t, J = 7.3 Hz, 3H, CH2CH3), 1.60 (s, 6H, 2 3CH3), 4.09 (s, 3H, 2-CH3), 4.55 (q, J = 7.3 Hz, 2H, CH2CH3), 8.04 (d, J = 8.5 Hz, 1H, 6-H), 8.23 (d, J = 8.5 Hz, 1H, 7-H), 8.38 (s, 1H, 4-H). 13 C NMR (100 MHz, Me2SO-d6): d 12.6 (CH2CH3), 14.6 (CH3), 21.6 (2 CH3), 43.6 (CH2CH3), 54.8 (C-3), 116.5 (C-7), 121.2 (d, J = 10 Hz, C-4), 123.9 (q, J = 270 Hz, CF3), 126.7 (d, J = 10 Hz, C-6), 129.6 (q, J = 30 Hz, C-5), 143.1, 143.8, 199.6 (C-2). 19F NMR (376 MHz, Me2SO-d6): d -62.92 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C14H17F3N+ 256.1308 [M I]+; found 256.1310. 4.3.4. 10 ,30 ,30 -Trimethyl-6-nitro-50 -(trifluoromethyl)-10 ,3,30 ,4tetrahydrospiro[chromene-2,20 -indole] 11a A stirred solution of iodide 9a (0.4 g, 1.08 mmol) in distilled water (20 mL) was treated with Na2CO3 (0.23 g, 2.16 mmol) at rt. The mixture became turbid immediately and was extracted with Et2O (3 15 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford crude intermediate enamine 10a as a brownish oil. This crude product was dissolved in CH3CN (3 mL), 2-chloromethyl-4-nitrophenol (0.2 g, 1.08 mmol) was added and the mixture was stirred under relux for 8 h. Then, the reaction mixture was allowed to reach room temperature and poured into water (40 mL). The separated product was extracted with Et2O (3 15 mL), combined extracts were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was subjected to flash chromatography on silica gel (hexane/acetone 9:1 v/v) to give the title compound 11a as a pale yellow crystalline solid (0.12 g, 32%); mp 154–155 8C (from acetonitrile). IR (KBr), n (cm1): 3075 (C-arom), 2972 (C-alif), 1513 (NO2-asymm), 1340 (C–F), 1327 (NO2-symm), 1112 (C–F), 967, 843, 638, 480. 1H NMR (400 MHz, CDCl3): d 1.26 (s, 6H, 2 30 CH3), 2.36–2.39 (m, 2H, CH2), 2.90 (s, 3H, N–CH3), 3.07–3.08 (m, 2H, CH2), 6.61 (d, J = 8.2 Hz, 1H, 70 -H), 6.79 (d, J = 9.0 Hz, 1H, 8-H), 7.24 (d, J = 1.8 Hz, 1H, 40 -H), 7.46 (ddd, J = 8.2, 1.8, 0.9 Hz, 1H, 60 -H), 8.00 (dd, J = 9.0, 2.8 Hz, 1H, 7-H), 8.05 (d, J = 2.8 Hz, 1H, 5-H). 13C NMR (100 MHz, CDCl3): d 21.8 (30 -CH3), 23.3 (CH2), 24.0 (CH2), 25.6 (30 CH3), 28.4 (N–CH3), 49.5 (C-30 ), 104.2 (C-spiro), 106.6 (C-70 ), 116.9 (C-8), 118.5 (q, J = 4 Hz, C-40 ), 121.1 (q, J = 30 Hz, C-50 ), 121.3 (C– NO2), 124.4 (C-7), 125.3 (C-5), 126.0 (q, J = 4 Hz, C-60 ), 125.1 (q, J = 270 Hz, CF3), 137.5 (C), 140.9 (C), 151.3 (C), 161.4 (C). 19F NMR (376 MHz, CDCl3): d 63.84 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C20H20F3N2O3+ 393.1421 [M + H]+; found 393.1423.
39
NMR spectra of compound 11a in TFA-d (trifluoroacetate 13): H NMR (400 MHz, TFA-d): d 1.83 (s, 6H, 2 3-CH3), 3.33–3.37 (m, 2H, CH2), 3.61–3.65 (m, 2H, CH2), 4.34 (s, 3H, N-CH3), 7.15 (d, J = 9.0 Hz, 1H, 30 -H), 7.93 (d, J = 8.5 Hz, 1H, 7-H), 8.02 (d, J = 1.5 Hz, 1H, 4-H), 8.05 (dd, J = 8.5, 1.5 Hz, 1H, 6-H), 8.29 (dd, J = 9.0, 2.7 Hz, 1H, 40 -H), 8.36 (d, J = 2.7 Hz, 1H, 60 -H). 13C NMR (100 MHz, TFA-d): d 22.4 (2 3-CH3), 28.9 (CH2), 29.0 (CH2), 36.3 (N–CH3), 57.4 (C-3), 116.9 (C-7), 117.9 (C-30 ), 122.1 (q, J = 10 Hz, C-4), 124.6 (q, J = 270 Hz, C-5), 126.8 (C), 127.8 (C-40 ), 128.3 (C-60 ), 129.0 (q, J = 10 Hz, C-6), 135.8 (q, J = 270 Hz, CF3), 142.4 (C), 143.8 (C), 145.5 (C), 162.7 (C), 201.3 (C-2). 1
4.3.5. 10 -Ethyl-30 ,30 -dimethyl-6-nitro-50 -(trifluoromethyl)-10 ,3,30 ,4tetrahydrospiro[chromene-2,20 -indole] 11b Following the preparation of 11a, a solution of iodide 9b (1.0 g, 2.6 mmol) in distilled water (20 mL) was treated with Na2CO3 (0.55 g, 5.2 mmol) to afford the crude intermediate enamine 10b as a brownish oil. The crude product 10b was then treated with 2chloromethyl-4-nitro-phenol (0.4 g, 2.09 mmol) in acetonitrile (5 mL) and the workup gave the titled compound 11b as white crystals (0.32 g, 42%); mp 177–178 8C (from acetonitrile). IR (KBr), n (cm1): 3074 (C-arom), 2970 (C-alif), 1519 (NO2-asymm), 1337 (C–F), 1327 (NO2-symm), 1112 (C–F), 806, 748, 637, 485. 1H NMR (400 MHz, CDCl3): d 1.23 (t, J = 5.3 Hz, 3H, CH2CH3), 1.25 (s, 3H, 30 CH3), 1.27 (s, 3H, 30 -CH3), 2.28 (td, J = 14.0, 5.3 Hz, 1H, 1/2 CH2), 2.45 (ddd, J = 14.0, 5.3, 2.8 Hz, 1H, 1/2 CH2), 3.03 (ddd, J = 14.0, 5.3, 2.8 Hz, 1H, 1/2 CH2), 3.21–3.07 (m, 1H, 1/2 CH2), 3.30 (tt, J = 14.7, 7.1, 1H, 1/2 CH2CH3), 3.42 (dq, J = 14.7, 7.1, 1H, 1/2 CH2CH3), 6.59 (d, J = 8.5 Hz, 1H, 70 -H), 6.77 (d, J = 9.0 Hz, 1H, 8-H), 7.23 (d, J = 1.8 Hz, 1H, 40 -H), 7.44 (dd, J = 8.5, 1.8 Hz, 1H, 60 -H), 7.99 (dd, J = 9.0, 2.8 Hz, 1H, 7-H), 8.05 (d, J = 2.8 Hz, 1H, 5-H). 13C NMR (100 MHz, CDCl3): d 14.7 (CH3CH2), 21.8 (30 -CH3), 23.5 (CH2), 24.7 (CH2), 25.7 (30 -CH3), 37.4 (CH3CH2), 49.6 (C-30 ), 104.4 (C-spiro), 105.7 (C-70 ), 116.9 (C-8), 118.6 (q, J = 10 Hz, C-40 ), 120.7 (q, J = 30 Hz, C-50 ), 121.2 (C-NO2), 124.4 (C-7), 125.3 (C-5), 125.1 (q, J = 270 Hz, CF3), 126.1 (q, J = 10 Hz, C-60 ), 137.3 (C), 140.8 (C), 150.2 (C), 161.3 (C). 19F NMR (376 MHz, CDCl3): d 63.77 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C21H22F3N2O3+ 407.1577 [M + H]+; found 407.1580. 4.3.6. 10 -Allyl-30 ,30 -dimethyl-6-nitro-50 -(trifluoromethyl)-10 ,3,30 ,4tetrahydrospiro[chromene-2,20 -indole] 11c A mixture of compound 6 (2.0 g, 8.8 mmol) with allyl bromide (3.19 g, 26.4 mmol) was heated under reflux for 24 h. The resultant crystalline bromide 9c was isolated by filtration, washed with ethanol (2 mL), dried and dissolved in distilled water (20 mL). To this solution, Na2CO3 (0.51 g, 4.8 mmol) was added, the separated material was extracted with Et2O (3 15 mL), the combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford crude intermediate enamine 10c as a reddish oil. The obtained product was dissolved in CH3CN (5 mL), 2chloromethyl-4-nitrophenol (0.305 g, 1.625 mmol) was added and the mixture was stirred under reflux for 8 h. Standard workup of the reaction mixture and purification of the product by column chromatography gave the title compound 11c as white crystals (0.29 g, 46%); mp 152–153 8C (from acetonitrile). IR (KBr), n (cm1): 3058 (C-arom), 2973 (C-alif), 1524 (NO2-asymm), 1345 (C–F), 1328 (NO2-symm), 1115 (C–F), 965, 840, 750, 638, 482. 1H NMR (400 MHz, CDCl3): d 1.28 (s, 3H, 30 -CH3), 1.32 (s, 3H, 30 -CH3), 2.21 (td, J = 14.0, 5.3 Hz, 1H, 1/2 CH2), 2.46 (ddd, J = 14.0, 5.3, 2.8 Hz, 1H, 1/2 CH2), 3.01 (ddd, J = 17.0, 5.3, 2.8 Hz, 1H, 1/2 CH2), 3.13 (ddd, J = 18.1, 13.3, 5.3 Hz, 1H, 1/2 CH2), 3.80 (ddt, J = 18.1, 4.2, 1.9 Hz, 1H, 1/2 N–CH2), 4.00 (ddt, J = 18.1, 4.2, 1.9 Hz, 1H, 1/2 N– CH2), 5.17 (dq, J = 10.3, 1.8 Hz, 1H, 1/2 CH2CH5 5CH2), 5.25 (dq, J = 17.1, 1.8 Hz, 1H, 1/2 CH2CH5 5CH2), 5.91 (ddt, J = 17.1, 10.3 4.5 Hz, 1H, CH2CH5 5CH2), 6.56 (d, J = 8.5 Hz, 1H, 70 -H), 6.78
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(d, J = 9.0 Hz, 1H, 8-H), 7.24–7.26 (m, 1H, 40 -H), 7.40–7.45 (m, 1H, 60 -H), 8.00 (dd, J = 9.0, 2.8 Hz, 1H, 7-H), 8.04 (d, J = 2.8 Hz, 1H, 5-H). 13 C NMR (100 MHz, CDCl3): d 21.9 (30 -CH3), 23.3 (CH2), 24.7 (CH2), 26.1 (30 -CH3), 45.4 (N-CH2), 49.6 (C-30 ), 104.3 (C-spiro), 106.6 (C-70 ), 115.8 (CH2CH5 5CH2), 116.9 (C-8), 118.6 (q, J = 10 Hz, C-40 ), 121.1 (C–NO2), 121.2 (q, J = 30 Hz, C-50 ), 124.3 (C-7), 125.1 (q, J = 270 Hz, CF3), 125.3 (C-5), 126.0 (q, J = 10 Hz, C-60 ), 134.2 (CH2CH5 5CH2), 137.3 (C), 140.9 (C), 150.5 (C), 161.2 (C). 19F NMR (376 MHz, CDCl3): d 63.84 (s, 3F, CF3). HRMS (ESI), m/z: calcd. for C22H22F3N2O3+ 419.1577 [M + H]+; found 419.1576. Acknowledgements This research was funded by a grant (No. MIP-022/2013) from the Research Council of Lithuania.
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