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N‑Alkylated 1,4-Diazabicyclo[2.2.2]octane−Polyethylene Glycol Melt as Deep Eutectic Solvent for the Synthesis of Fisher Indoles and 1H‑Tetrazoles Sarfaraz Ali Ghumro,† Rima D. Alharthy,‡ Mariya al-Rashida,§ Shakil Ahmed,† Muhammad Imran Malik,*,† and Abdul Hameed*,† †
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan ‡ Department of Chemistry, Science and Arts College, King Abdulaziz University, Rabigh Campus, Jeddah 21589, Saudi Arabia § Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan S Supporting Information *
ABSTRACT: 1,4-Diazabicyclo[2.2.2]octane (DABCO)-based ionic liquids (ILs) 2−4 were synthesized by the N-alkylation of DABCO using alkyl halides of varying chain lengths (C2, C5, and C7). The N-alkylated DABCO-ILs were mixed with polyethylene glycols (PEGs) of varying molar masses as hydrogen bond donors (HBDs) to prepare new deep eutectic solvents (DESs). These DABCO−PEG-based DESs were successfully employed for the synthesis of a variety of indoles 7a−7h (by Fischer indole synthesis) and 1H-tetrazoles 9a−9i (by click chemistry). For comparison, DESs of DABCO-ILs with different alcohols (as HBD) were also prepared and investigated for the synthesis of indoles. Although comparable yields were observed in DES-containing alcohols and PEGs, the use of PEG as HBD in DES (as an alternative to alcohols) provides a much safer, nonvolatile, and environmentally benign reaction medium for synthetic reactions. The first successful application of PEGpolymer-based DES as benign reaction media for organic syntheses offers exciting opportunities to be explored in the realm of green synthesis.
1. INTRODUCTION One of the milestones to be achieved in the green synthetic chemistry is geared toward the efforts to minimize hazardous impact of volatile solvents on the environment.1 One of the greatest challenges in this regard is the substitution of obnoxious volatile solvents with green, environment-friendly, nontoxic, and nonvolatile reaction media. Introduction of ionic liquids (ILs) as an environment-friendly medium for organic reactions has been a major step in this direction.2 Important properties of ILs in this context include low volatility, high thermal stability, efficient recyclability, and nonflammability.1a,3 A variety of synthetic reactions have been reported in ILs where they act as both solvents and catalysts.4 The most widely used ILs for organic syntheses are those based on imidazole or pyridine.1a,5 However, the inertness of imidazole6 and the toxicity of pyridine hamper their use for the synthesis of drugs and other bioactive molecules because they require major postsynthesis purification and separation steps. Moreover, they have a single functionalized nitrogen atom to act as a catalyst. On the other hand, 1,4-diazabicyclo[2.2.2]octane (DABCO) is endowed with two active nitrogen atoms. Because DABCO exists in a solid form, it offers ease of handling and is also significantly less toxic than pyridine. DABCO serves as a catalyst in many organic transformations such as ring opening © 2017 American Chemical Society
of aziridine with amines or thiols, synthesis of quinoxalines, and so forth.7 Hasaninejad et al. reported the use of silica-bonded npropyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride (SBDABCO) as a catalyst to perform the three-component reaction for the synthesis of 4H-benzo[b]pyran derivatives.8 In some recent studies, a complex of DABCO−palladium supported on silica or polymer has been used to catalyze crosscoupling reactions, that is, Suzuki−Miyaura and Mizoroki− Heck reactions.9 In the present study, DABCO was functionalized by the reaction with alkyl halides to obtain the corresponding Nalkylated quaternary ammonium salts (or ILs) (2−4). Furthermore, the DABCO-based ILs were mixed with hydrogen bond donors (HBDs) to develop novel deep eutectic solvents (DESs). The DESs can be considered to be unique type of ILs, where the individual solid components, when mixed together in a specific ratio, undergo a significant depression in the melting point resulting in a low melting (eutectic) mixture.10 The HBD component of the DES plays an important role in this depression of melting point. Received: May 17, 2017 Accepted: June 12, 2017 Published: June 22, 2017 2891
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Table 1. Percentage Yield of Indole 7a in Different DESs (DABCO-ILs/HBD)
spectrometry. The synthesized DABCO-based ionic salts (2− 4) were mixed and heated with HBDs (alcohols or PEGs of varying molar masses) to form melts as DESs, which were utilized for Fisher indole and 1H-tetrazole synthesis. Fisher indole synthesis in pyridine- or imidazole-based ILs has been reported.12 Recently, König et al. have described the Fisher indole synthesis in the low melting mixture of tartaric acid/dimethyl urea (3:7) as DES.13 In this study, we report DABCO-based new ILs 2−4 that were mixed with methanol, a common HBD source, to prepare DESs for the Fisher indole synthesis. The percentage yield of indole 7a in DABCO-ILs 3 and 4 was good (entry number 1−3, Table 1). Comparable yields of indole 7a were obtained for the reaction in PEG-based DES (Table 1). Moreover, the synthesis of indole 7a was also carried out by using alone DABCO-based ILs 3 and 4. The percentage yield of indole 7a obtained by performing the reaction at 80 °C up to 2.5 h in DABCO-ILs 3 and 4 was 50 and 56%, respectively. The formation of indole 7a in ethanol, as the solvent, without any catalyst was found to be 47%. These results show the significant importance of DES melts (Table 1) as a solvent to preform indole formation. The use of PEG as an HBD source in DESs offers safer, nonvolatile, and environmentally benign reaction media (Scheme 2). DABCO-IL 3 (1,4-dipentyl-1,4-diazabicyclo[2.2.2]octane1,4-diium bromide) was used as a model IL to prepare DESs with a range of different alcohols and PEGs (as HBDs) in the molar ratio of 1:2 (Table 2). These model DESs were employed as the medium to act as solvents and catalysts simultaneously for the Fisher indole reaction. The yield of indole 7a was comparatively less in low boiling alcohols (entries 1−5, Table 2) compared to that in the high boiling alcohols (entries 6−10, Table 2). However, isolation of the product from the DES of high boiling alcohols was slightly difficult and
Physiochemical properties of DES, such as nontoxicity, nonvolatility, biodegradability, and recyclability, are similar to those of ILs.11 The DESs are an excellent substitute of traditional organic solvents in synthetic organic chemistry.10a Herein, the use of polymers [polyethylene glycol (PEG)] as HBD to formulate DESs for indole and 1H-tetrazole synthesis is reported for the first time. Numerous mono- and polyhydric alcohols (typical HBDs) are used to compare the efficiency of polymer-based DESs. Comparative yields of 2,3,4,9-tetrahydro-1H-carbazole (indole) 7a with PEG as HBD are presented in Table 1. The application of PEGs in DES as HBD provides safer, environment-friendly, and nonvolatile reaction media for organic synthesis. ILs and HBDs are associated with each other via hydrogen-bonded interactions in DESs.10
2. RESULTS AND DISCUSSION DABCO-based ILs 2−4 were prepared via simple N-alkylation with different alkyl (C2, C5, and C7) halides (Scheme 1). Structures of the prepared ionic salts were confirmed with different spectroscopic techniques including infrared (IR), proton nuclear magnetic resonance (1H NMR), and mass Scheme 1. Synthesis of DABCO-Based Ionic Liquids 2−4
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Scheme 2. Synthesis of Indoles in DABCO-IL-Based DESs
such a hindered and substituted product confirms the validity of new catalytic DES melts for its application as safe and green reaction media for organic syntheses. Tetrazole is a biologically active molecule. There are many pharmaceutically important molecules15 that contain a tetrazole moiety and exhibit diverse biological applications and improved pharmacokinetic properties.16 Click reaction for the formation of 1H-tetrazole via [2 + 3]nitrile−azide coupling has emerged as a powerful synthetic approach in organic synthesis. Since the advent of this reaction by Demko and Sharpless,17 a wide range of different reagents/reaction media have been utilized for this reaction.18 In the current study, we employed a novel DES, mixture of DABCO-IL 3 and PEG400, for click reaction leading to the synthesis of 1H-tetrazole. A typical reaction between pmethoxy benzonitrile and sodium azide was conducted in DES at high temperature (118−121 °C). Sodium azide (NaN3) serves as a safe source of azide species owing to its solid nature and easy handling. After aqueous workup and purification steps, product 9a was obtained in a satisfactory yield (50%). A reaction between 3-acetyl benzonitrile and sodium azide in the presence of only DABCO-IL 3 up to 8 h to form corresponding 1H-tetrazole gave low yield (10%), whereas the click reaction in the only solvent (EtOH) gave no corresponding product (9g) because of the solubility issue of sodium azide in ethanol. The results signify the importance of our DABCO-based DES melt as a solvent to perform the click reactions. The scope of DABCO-IL 3-based DES (Table 2, entry 21) was expanded by the reaction of different substituted benzonitriles with NaN3 to get corresponding 1H-tetrazoles 9a−9h in variable yields (Figure 2). The yields of 4′-fluoro 9d (52%) and 4′-methoxy 9a (50%) phenyl-substituted tetrazoles were found to be the highest among the series. 4′-Chloro 9b and 4′-bromo 9f phenyl-substituted tetrazoles were produced in modest yields, 45 and 43%, respectively, whereas the synthesis of 4′-methylsubstituted tetrazole 9e has unexpectedly low yield (39%) among the series. The yield of 2′-methyl-substituted tetrazole 9c was also low (40%), which may be due to the steric hindrance of the ortho methyl group at the phenyl ring. Furthermore, the tetrazoles having 3′-acetyl 9g (44%) and 3′methyl 9i (43%) substituents on the phenyl ring were also obtained in modest yields. Moreover, the unsubstituted phenyl 1H-tetrazole 9h was formed in 44% yield. Overall, the yields of substituted phenyl 1H-tetrazoles were found to be between 52 and 39% (Figure 2). The successful synthesis of indoles and 1H-tetrazoles in DABCO−PEG-based DESs showed the application of PEGs as HBD in DES in combination with ILs. The use of PEG in DES has an additional benefit of avoiding volatile solvent to develop green and eco-friendly reaction media. Moreover, the thermal stability of DABCO-based ILs 2−4 was determined by thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC).
tedious. DESs based on butanol (entry 4, Table 2) or hexanol (entry 5, Table 2) proved to be a better compromise owing to their less volatility and easy removal of alcohol during purification (Table 2). Moreover, the use of diols, triols, and polyols (entries 11−19, Table 2) as the HBD component in DESs resulted in comparable yields of indole 7a. The major advantages of the use of diols, triols, and polyols as HBDs include less volatility and easy removal via facile aqueous workup of the reaction mixture. The use of PEG of the varying molar mass, as a substitute for traditional HBD source, provides a nonvolatile and less toxic reaction medium, an imperative aspect for green chemistry. Employing PEG as HBD in DES melts as the reaction media in the synthesis is unprecedented (entries 20−29, Table 2), to the best of our knowledge. IL 3 was mixed with PEGs of different molar masses to form DES melts that were then explored for their scope in the synthesis of indole 7a (Table 2). The highest yield was obtained in the DES based on IL 3 and PEG400 (entry 21, Table 2), which was comparable to that obtained in IL− alcohol melt (entry 4, Table 2). The yield of indole decreased with increasing molar mass of PEG used in DES preparation (i.e., entries 23, 25, and 27). This decrease was most significant for PEG20000- and PEG40000-based DES. High molar mass polymers were also difficult to remove from the reaction mixture. The scope of polymer-based DES was explored by carrying out the synthesis of various substituted indoles (7a−7f, Figure 1). In this regard, a mixture of DABCO-IL 3 and PEG400 as DESs was used as a model reaction medium to carry out the reactions between different substituted phenyl hydrazines and cyclohexanone to form the corresponding substituted indoles 7a−7f (Figure 1). The reaction of cyclohexanone with 4′-methoxy-substituted phenyl hydrazine proceeded smoothly in DABCO-based DES (entry 22, Table 2) to give indole 7b in excellent yield (83%). However, the yield of indole 7c (60%) dropped with 4′-cyano (−CN)-substituted phenyl hydrazine, possibly because of the electron-withdrawing effect of the −CN group. Moreover, the yields of the indoles 7d (62%) and 7e (50%) were relatively less because of the presence of chloro and methyl substituents at the ortho position that resulted in significant hindrance in a [3,3]-sigmatropic rearrangement to furnish the corresponding indoles. The reaction of cyclohexanone with 4′-fluorosubstituted phenyl hydrazine also gave excellent yield (84%) (Figure 1). The reaction between L-menthol and phenyl hydrazine was also performed in the newly developed DABCOIL-based DES to get the corresponding indole. The product obtained in L-methanol was identified as indolenine rather than indole and is in agreement with the previous reports.14 The requisite cyclization to furnish tricycle ring system occurs at isopropyl-substituted carbon to form indolenine 7g as the major isomer and 7h as the minor isomer.14 The formation of 2893
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Table 2. DABCO-Based Ionic Salts in Combination with Various HBDs for the Fisher Indole Synthesis of 7a
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Table 2. continued
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Table 2. continued
Figure 2. Synthesis of substituted 1H-tetrazoles 9a−9h in DABCO− PEG-based DESs.
Figure 1. Synthesis of substituted 2,3,4,9-tetrahydro-1H-carbazole (indoles) 7a−7f or indolenine 7g, 7h in DABCO-IL-based DES melt.
decomposition temperatures (235 °C 2, 230 °C 3, and 255 °C 4, respectively) (Figures 3 and S1).
Figure 3a shows the overlap of TGA graph and its first derivative (DTG) for DABCO-IL 3, and Figure 3b shows the overlap of its TGA and DSC graphs. In the first step, there is a weight loss of about 37% in the temperature range from ambient to 110 °C, and the corresponding DSC data in this range suggest that an endothermic process is associated with this change. This weight loss is most likely due to the loss of water molecules. After initial loss of water, the weight remains stable until being heated up to 215 °C, after which a sharp decrease in weight (28%) is observed; this is the first decomposition temperature, 230 °C, as indicated by the DTG. According to DSC, this weight loss is also an endothermic process and is probably due to the loss of alkyl chains. Immediately after this step, a gradual weight loss of about 32% is observed, which corresponds to the second decomposition temperature of 290 °C as indicated by the DTG. Similar to the previous step, this was also an endothermic process as can be seen from the DSC graph. The thermal data of DABCO-ILs (2, 4) have been included in Figure S1. The DABCO-based ILs (2−4) were found to have sufficiently high
3. CONCLUSIONS In conclusion, DABCO-based ILs 2−4 were synthesized and mixed with different alcohols and PEGs of varying molar masses as HBD to prepare DESs for organic reactions including indole and 1H-tetrazole synthesis. The optimized DES, made up of IL 3 and PEG400, was explored further for the synthesis of different indoles (7a−7h) to validate the scope of IL−PEGbased DES. The DES melt was also used to perform the click reaction for the synthesis of 1H-tetrazoles (9a−9i). The use of PEGs of varying molar masses as HBD in DES proved to be a safer and environmentally friendly reaction medium and opens new avenue for further research in this area. 4. EXPERIMENTAL SECTION 1DABCO (≥99.0%), ethyl iodide, pentyl bromide, heptyl bromide, and toluene (≥99.5%) were purchased from SigmaAldrich and used without any purification unless otherwise stated. Thin layer chromatography (TLC) was carried out using silica gel 60 aluminum-backed plates 0.063−0.200 mm. 2896
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characterized using 1H, 13C NMR, IR, UV spectroscopy, and mass spectrometry. 4.2. Spectral Data of DABCO-Based Ionic Liquids. 4.2.1. 1,4-Diethyl-1,4-diazabicyclo[2.2.2]octane-1,4-diium Iodide (2). Light yellow (1.70 g, 90%). mp 234−236 °C, IR (νmax, cm−1): (solid) 3464, 2969, 2892, 1739, 1620, 1465, 1388, 1262, 1124, 1056, 976. 1H NMR (400 MHz, DMSO): δH 3.83 (12H, s, CH2 × 6), 3.58 (4H, q, J = 7.2 Hz, CH2 × 2), 1.82 (6H, t, J = 7.2 Hz, CH3 × 2); 13C NMR (75 MHz, DMSO): δC 59 (CH2 × 2), 50 (CH2 × 6), 9.8 (CH3 × 2); MS-EI m/z 297.0 (M+ − I−), 169.1 (M+ − 2I− − H). 4.2.2. 1,4-Dipentyl-1,4-diazabicyclo[2.2.2]octane-1,4diium Bromide (3). DABCO (1.0 g, 8.92 mmol, and 1 equiv) was treated with pentyl bromide (2.94 g, 19.6 mmol, and 2.2 equiv). Then following the general procedure, the corresponding DABCO-IL 3 was obtained as yellow thick oil (3.15 g, 86%). IR (νmax, cm−1): (solid) 3424, 2959, 2869, 2510, 2056, 1631, 1467, 1390, 1321, 1211, 1117, 1057, 855. 1H NMR (400 MHz, DMSO): δH 3.90 (12H, s, CH2 × 6), 3.60−3.57 (4H, app t, J = 8.4 Hz, CH2 × 2), 1.71−1.65 (4H, m, CH2 × 2), 1.35− 1.24 (8H, m, CH2 × 4), 0.88 (6H, t, J = 6.8 Hz, CH3 × 2); 13C NMR (75 MHz, DMSO): δC 63.4 (CH2 × 2), 50.3 (CH2 × 6), 27.6 (CH2 × 2), 21.6 (CH2 × 2), 20.9 (CH3 × 2), 13.6 (CH3); MS-ESI m/z (%), 333.1 (M+ − Br−), 335.1. 4.2.3. 1,4-Diheptyl-1,4-diazabicyclo[2.2.2]octane-1,4diium Bromide (4). DABCO (500 mg, 4.46 mmol, and 1 equiv) was treated with heptyl bromide (1.75 g, 8.92 mmol, and 2.2 equiv). Then following the general procedure, the corresponding DABCO-IL 4 was obtained as light yellow thick oil (1.74 g, 84%). IR (νmax, cm−1): (solid) 3417, 2927, 2861, 1630, 1389, 1315, 1202, 1116, 853. 1H NMR (400 MHz, DMSO): δH 3.90 (12H, s, CH2 × 6), 3.56−3.51 (4H, m, CH2 × 2), 1.68 (4H, app brs, CH2 × 2), 1.35−1.24 (16H, m, CH2 × 4), 0.86 (6H, t, J = 6.4 Hz, CH3 × 2); 13C NMR (75 MHz, DMSO): δC 63.3 (CH2 × 2), 50.3 (CH2 × 6), 30.9 (CH2 × 2), 28.0 (CH2 × 2), 25.4 (CH2 × 2), 21.9 (CH2 × 2), 21.3 (CH2 × 2), 13.8 (CH3); MS-ESI m/z (%), 389.2 (M+ − Br−), 391.1. 4.3. Procedure for the Synthesis of Substituted Tetrahydro-1H-carbazole (Indoles/Indolenines). In a general procedure, an oven-dried round-bottom flask was charged with DABCO-IL 5 and HBD (alcohol or PEG polymer) in a ratio of 1:2, respectively. The mixture was heated at 80 °C to homogenize it, and then to this mixture corresponding phenyl hydrazine hydrochloride (1 mmol and 1 equiv) and cyclohexanone (1 mmol and 1 equiv) were added. The resulting reaction mixture was heated at reflux (78−80 °C) until the complete consumption of phenyl hydrazine (the starting material), as monitored by TLC by using the eluant mixture of EtOAc and hexane. Upon the complete consumption of the starting material, the reaction mixture was cooled to room temperature and then crashed ice was added to the reaction flask. The resulting mixture was stirred to get precipitates that were filtered and washed with cold distilled water to get the desired product (7a−7h). For some samples, silica gel column chromatography with the gradient eluant mixture of EtOAc and hexane (1:9 to 9:1) was used to purify the product. 4.3.1. 2,3,4,9-Tetrahydro-1H-carbazole (7a). Yield 70% 1H NMR (400 MHz, DMSO): δH 10.58 (1H, s, NH), 7.30 (1H, d, J = 7.6 Hz, ArH), 7.20 (1H, d, J = 8 Hz, ArH), 6.96 (1H, t, J = 7.2 Hz, ArH), 6.89 (1H, t, J = 7.6 Hz, ArH), 2.68 (2H, t, J = 5.6 Hz, CH2), 2.60 (2H, t, J = 5.4 Hz, CH2), 1.82−1.79 (4H, m,
Figure 3. (a) Overlap of TGA (blue) and DTG (purple) graphs for DABCO-IL 3 and (b) overlap of TGA (blue) and DSC (green) graphs for DABCO-IL 3.
Analytical grade solvents such as dichloromethane, ethyl acetate (EtOAc), diethyl ether, hexane, methanol, and so forth were used. Short-wavelength ultraviolet (UV) radiation at 254 nm was used for the visualization of TLC plates. Staining mixtures such as basic potassium permanganate or vanillin were also used for spot visualization on TLC plates. IR spectra were recorded on a Bruker Vector-22 spectrometer. The 1H NMR spectra were recorded on Bruker spectrometers at 300, 400, and 500 MHz, whereas the carbon magnetic resonance (13C NMR) spectra were recorded at 75, 100, and 125 MHz in deuterated dimethyl sulfoxide (DMSO)-d6. The chemical shifts were recorded on the δ-scale (ppm) using residual solvents as an internal standard (DMSO; 1H 2.50, 13C 39.43).19 Coupling constants were calculated in hertz; the multiplicities were labeled as s (singlet), d (doublet), t (triplet), q (quartet), and quint (quintet); and the prefixes br (broad) or app (apparent) were used. Mass spectra (EI+ and ESI+) were recorded on Finnigan MAT-321A, Germany. Preparative high-performance liquid chromatography (HPLC) (JAI model number LC-908) having a UV−vis detector was used for the purification of the compounds (7g and 7h). A normal-phase silica-D-60 column (20 mm × 250 mm, 5 μm particle size) with a flow rate of 3 mL/min was used. 4.1. General Synthetic Procedure for DABCO-Based Ionic Fluoride Salts. In a typical reaction, DABCO (500 mg, 4.46 mmol, and 1 equiv) was added to the oven-dried roundbottom flask along with the solvents toluene/dichloromethane (3:5). To the resulting solution, the corresponding ethyl iodide (1.50 g, 9.68 mmol, and 2.2 equiv) was added at room temperature and heated at reflux (118−120 °C) until no starting material was observed on the TLC analysis. On cooling, the resulting ionic salt was separated and washed further with cold toluene and dried in vacuo. The obtained material was further washed with cold toluene (10 mL × 3) to get the final desired products DABCO-ILs (2−4). All ionic salts were 2897
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CH2 × 2); MS-EI m/z 171.1 (M+). The data are identical to that previously reported.20 4.3.2. 6-Methoxy-2,3,4,9-tetrahydro-1H-carbazole (7b).21 Yield 83% 1H NMR (300 MHz, DMSO): δH 10.39 (1H, s, NH), 7.08 (1H, d, J = 8.7 Hz, ArH), 6.80 (1H, d, J = 2.4 Hz, ArH), 6.59 (1H, dd, J = 8.7, 2.4 Hz, ArH), 3.72 (1H, s, OCH3), 2.63 (2H, t, J = 5.7 Hz, CH2), 2.60 (2H, t, J = 5.4 Hz, CH2), 1.79−1.77 (4H, m, (CH2)2); MS-EI m/z 201 (M+). 4.3.3. 6-Cyano-2,3,4,9-tetrahydro-1H-carbazole (7c). Yield 62% 1H NMR (300 MHz, DMSO): δH 11.27 (1H, s, NH), 7.83 (1H, s, ArH), 7.38 (1H, d, J = 8.4 Hz, ArH), 7.31 (1H, dd, J = 8.4, 1.5 Hz, ArH), 2.69 (2H, app t, J = 6.4 Hz, CH2), 2.64 (2H, t, J = 5.7 Hz, CH2), 1.81−1.74 (4H, m, CH2−CH2); MS-EI m/ z 196.1 (M+). 4.3.4. 8-Chloro-2,3,4,9-tetrahydro-1H-carbazole (7d).12a Yield 76% 1H NMR (400 MHz, DMSO): δH 10.39 (1H, s, NH), 7.28 (1H, d, J = 6.6 Hz, ArH), 7.02 (1H, d, J = 7.2 Hz, ArH), 6.91 (1H, t, J = 7.7 Hz, ArH), 2.71 (1H, app t, J = 5.7 Hz, CH2), 2.60 (1H, app t, J = 5.7 Hz, CH2), 1.80−1.78 (4H, m, CH2−CH2); MS-EI m/z 205.1 (M+). 4.3.5. 8-Methyl-2,3,4,9-tetrahydro-1H-carbazole (7e).12c Yield 64% 1H NMR (300 MHz, DMSO): δH 10.48 (1H, s, NH), 7.12 (1H, d, J = 6.9 Hz, ArH), 6.80 (1H, t, J = 7.4 Hz, ArH), 6.75 (1H, d, J = 6.6 Hz, ArH), 2.70 (2H, app t, J = 5.7 Hz, CH2), 2.58 (2H, t, J = 5.4 Hz, CH2), 1.80−1.79 (4H, m, CH2−CH2); MS-EI m/z 185.1 (M+). 4.3.6. 6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole (7f).21 Yield 75% 1H NMR (300 MHz, DMSO): δH 10.69 (1H, s, NH), 7.19 (1H, dd, J = 8.4, 3.8 Hz, ArH), 7.04 (1H, dd, J = 10.0, 2.4 Hz, ArH), 6.76 (1H, td, J = 9.6, 2.7 Hz, ArH), 2.67 (2H, t, J = 5.4 Hz, CH2), 2.56 (2H, t, J = 5.4 Hz, CH2), 1.82− 1.75 (4H, m, CH2−CH2); MS-EI m/z 189.1 (M+). 4.3.7. (2R,4aR)-4a-Isopropyl-2-methyl-2,3,4,4a-tetrahydro1H-carbazole (7g).14 Following the general procedure, the reaction was performed, and the corresponding compounds (7g and 7h) were isolated by using preparative HPLC with the eluant mixture of EtOAc and hexane (4:6). Yield 39% 1H NMR (300 MHz, DMSO): δH 7.44 (1H, d, J = 7.5 Hz, ArH), 7.36 (1H, d, J = 7.5 Hz, ArH), 7.28 (1H, t, J = 6.6 Hz, ArH), 7.13 (1H, t, J = 7.4 Hz, ArH), 2.64 (1H, dd, J = 13.2, 3.3 Hz, CH), 2.49 (1H, m, obscured by H2O signal, CH), 2.36 (1H, quint, J = 6.9 Hz, CH), 2.28 (1H, t, J = 12.3 Hz, CH), 1.53−1.51 (3H, m, CH2−CHH), 1.16 (3H, d, J = 6.9 Hz, CH3), 1.09 (3H, d, J = 5.4 Hz, CH3), 0.88−0.78 (1H, m, CH), 0.12 (3H, d, J = 6.9 Hz, CH3); MS-EI m/z 227.2 (M+). 4.3.8. (2R,4aS)-4a-Isopropyl-2-methyl-2,3,4,4a-tetrahydro1H-carbazole (7h).14 Yield 25% 1H NMR (300 MHz, DMSO): δH 7.46 (1H, d, J = 7.8 Hz, ArH), 7.36 (1H, d, J = 7.2 Hz, ArH), 7.28 (1H, td, J = 7.5, 0.9 Hz, ArH), 7.13 (1H, t, J = 7.2 Hz, ArH), 2.77 (1H, dd, J = 12.9, 6.0 Hz, CH), 2.42−2.32 (3H, m, CH2−CHH), 2.02 (1H, tt, J = 14.2, 4.2 Hz, CH), 1.30 (1H, app dd, J = 14.1, 1.8 Hz, CH), 1.16 (3H, d, J = 6.9 Hz, CH3), 1.05 (1H, td, J = 14.1, 3.9 Hz, CH), 0.71 (3H, d, J = 7.2 Hz, CH3), 0.11 (3H, d, J = 6.6 Hz, CH3); MS-EI m/z 227.2 (M+). 4.4. General Procedure for the Synthesis of Phenyl 1H-Tetrazoles 9a−9i. In a typical procedure, an oven-dried round-bottom flask was charged with DABCO-IL 3 and HBD (PEG400 polymer) in a ratio of 1:2, respectively. The mixture was homogenized by heating at 80 °C and then corresponding benzonitrile (1 mmol and 1 equiv) and sodium azide (3.5 mmol and 3.5 equiv) were added. The resulting reaction mixture was heated at 115−120 °C until the complete consumption of starting materials as monitored by the TLC
analysis. Furthermore, the reaction mixture was cooled to room temperature, diluted with EtOAc (2−3 mL), and then 5% HCl (5−8 mL) was added and stirred for a while to get the precipitates of the desired tetrazole. Some reaction mixtures were extracted with EtOAc (25 mL × 2). The organic layers were combined, dried with MgSO4, filtered, and evaporated in vacuo to get the 1H-tetrazole (9a−9i). 4.4.1. 5-(4′-Methoxyphenyl)-1H-tetrazole (9a).22 50% 1H NMR (300 MHz, DMSO): δH 7.97 (2H, d, J = 9.0 Hz, ArH), 7.14 (2H, d, J = 9.0 Hz, ArH), 3.83 (3H, s, OCH3); MS-EI m/z 176.1 (M+). 4.4.2. 5-(4′-Chlorophenyl)-1H-tetrazole (9b).22,23 45% 1H NMR (300 MHz, DMSO): δH 8.04 (2H, d, J = 8.7 Hz, ArH), 7.68 (2H, d, J = 8.4 Hz, ArH); MS-EI m/z 180.1 (M+). 4.4.3. 5-(2′-Methylphenyl)-1H-tetrazole (9c).24 40% 1H NMR (300 MHz, DMSO): δH 7.67 (1H, d, J = 7.5 Hz, ArH), 7.49−7.36 (3H, m, ArH), 2.46 (3H, s, CH3, obscured by DMSO signal); MS-EI m/z 160.1 (M+). 4.4.4. 5-(4′-Fluorophenyl)-1H-tetrazole (9d).25 52% 1H NMR (400 MHz, DMSO): δH 8.07 (2H, dd, J = 8.8, 5.6 Hz, ArH), 7.45 (2H, t, J = 8.8 Hz, ArH); MS-EI m/z 164.1 (M+). 4.4.5. 5-(4′-Methylphenyl)-1H-tetrazole (9e).22,24 39% 1H NMR (300 MHz, DMSO): δH 7.91 (2H, d, J = 8.1 Hz, ArH), 7.39 (2H, d, J = 8.1 Hz, ArH), 2.38 (3H, s, CH3); MS-EI m/z 160.1 (M+). 4.4.6. 5-(4′-Bromophenyl)-1H-tetrazole (9f).26 43% 1H NMR (400 MHz, DMSO): δH 7.96 (2H, d, J = 6.3 Hz, ArH), 7.79 (2H, d, J = 6.3 Hz, ArH); MS-EI m/z 223.9 (M+), 225.9. 4.4.7. 5-(3′-Acetylphenyl)-1H-tetrazole (9g). 44% 1H NMR (400 MHz, DMSO): δH 8.58 (1H, s, ArH), 8.28 (1H, d, J = 7.6 Hz, ArH), 8.16 (1H, d, J = 8.0 Hz, ArH), 7.77 (1H, d, J = 7.6 Hz, ArH), 2.66 (3H, s, CH3CO); MS-EI m/z 188.1 (M+). 4.4.8. 5-Phenyl-1H-tetrazole (9h).22 44% 1H NMR (400 MHz, DMSO): δH 8.04−8.02 (2H, m, ArH), 7.60−7.58 (3H, m, ArH); MS-EI m/z 146 (M+). 4.4.9. 5-(3′-Methylphenyl)-1H-tetrazole (9i).24 43% 1H NMR (300 MHz, DMSO): δH 7.78 (1H, brs, ArH), 7.73 (1H, d, J = 7.8 Hz, ArH), 7.23 (1H, t, J = 7.8 Hz, ArH), 7.03 (1H, d, J = 7.2 Hz, ArH), 2.325 (1H, s, CH3); MS-EI m/z 160.1 (M+).
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00618. Thermal analysis of DABCO-ILs (2, 4) and NMR spectra (Figures S2−S22) (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (M.I.M.). *E-mail:
[email protected], abdul.hameed@iccs. edu. Phone: 0092-21-99261701-2. Fax: 0092-21-3481901 (A.H.). ORCID
Mariya al-Rashida: 0000-0003-0832-1098 Muhammad Imran Malik: 0000-0001-6942-0407 Abdul Hameed: 0000-0003-0211-6819 Notes
The authors declare no competing financial interest. 2898
DOI: 10.1021/acsomega.7b00618 ACS Omega 2017, 2, 2891−2900
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ACKNOWLEDGMENTS The authors are thankful to Higher Education Commission (HEC), Pakistan for providing financial support under the “National Research Program for Universities” to project no. 5743.
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