BF₃@K10: An Efficient Heterogeneous Montmorillonite Catalyst for the Halogenation of N-Heterocycles

Honoring the contributions of the late Har Gobind Khorana in nucleic acid chemistry.

Abstract

Halogenated N-heterocycles are an essential structural building block in medicinal chemistry. Herein, we describe an economical and efficient protocol for the regioselective halogenation of several N-heterocycles (pyrimidines, a pyrazole, 2-aminopyridine, theophylline, and an imidazo[1,2-a]pyridine) with BF₃-doped montmorillonite (BF₃@K10). The new catalyst was characterized by FTIR and ¹¹B NMR spectroscopy, XRD, SEM, and EDS. The developed strategy provides easy and fast access to iodo-, bromo-, and chloro-N-heterocycles under mild conditions. This method was used to synthesize nine new halogenated pyrimidine derivatives. The reaction is simple and general, affording good to excellent yields of products under conventional heating or microwave conditions in the presence of BF₃@K10 as an ecofriendly, inexpensive, and efficient catalyst. This protocol is clearly superior to the conventional route because it offers short reaction times, high yields, and easy workup.

Sustainability is becoming increasingly important in nearly every chemical industry, because it will require the efficient use of resources to produce chemicals to meet the needs of today’s society and those of future generations. Green catalysis is an achievable strategy for accomplishing the goal of sustainable development. Its main goals are to reduce the environmental, human health, and safety risks of chemicals by redesigning toxic molecules, synthetic routes, and industrial processes.[1] For instance, the versatile properties of both natural and modified clays have received much attention owing to their application in the fabrication of catalysts. Montmorillonite (MMT) can efficiently act as a support to incorporate numerous guest species within its layers or on its external surface.[2] MMT K10 is categorized as a fascinating clay catalyst because it has several advantages over other solid supports.[3] It can act as a general Brønsted or Lewis acid, and it is considered to be a low-cost green catalyst[4] because it prevents waste and is reusable and safe to handle. Indeed, MMT can be recovered easily by filtration. It can be used under solvent-free conditions in a one-pot process and activated by microwave or ultrasound irradiation.[5] Microwave-assisted organic synthesis has been widely used in organic chemistry for the last 40 years to solve problems such as low yields, long reaction times, formation of byproducts, and efficient synthesis of libraries of compounds.[6] In 2014, Bamoniri and co-workers developed a green heterogeneous solid acid based on BF₃ embedded in silica nanoparticles for preparing formazan dyes under solvent-free conditions.[7] Similarly, silica-supported boron trifluoride (SiO₂·BF₃) was used as a catalyst for the synthesis of 14-aryl or alkyl-14H-dibenzo[a,j]xanthene derivatives by condensation of 2-naphthol and aldehydes.[8] The same heterogeneous catalyst was used to prepare 1,2,4,5-tetrasubstituted imidazoles.[9] Moreover, alumina-supported BF₃/γ-Al₂O₃ nanoparticles were prepared through the reaction of nano-γ-alumina with BF₃·Et₂O and were used for synthesizing some cyclic acetals under thermal- and solvent-free conditions.[10]

Halogenated heteroaromatic compounds are crucial building blocks for constructing carbon–carbon and carbon–heteroatom bonds in organic synthesis and drug design.[11] They play a pivotal role in drug and natural-product synthesis.[12] Furthermore, heteroaromatic bromides and iodides have been extensively used in cross-coupling[13] and Grignard[14] reactions. So far, several synthetic methods for 5-halouracil derivatives have been developed because of the spectral features of these compounds. For instance, Asakura and Robins have reported an efficient method for preparing 3′,5′-di-O-acetylated and unprotected 5-halouracil nucleosides by using elemental iodine or a lithium halogenide (LiI, LiBr, or LiCl) and ceric ammonium nitrate at 80 °C.[15] Knaus and co-workers have described a mild and efficient methodology for synthesizing 5-halo- (iodo-, bromo-, or chloro-) uracil nucleosides.[16] For instance, 5-halouridines and 5-haloarabinouridines were synthesized in good to excellent yields by the halogenation of 2′-deoxyuridine, uridine, and arabinouridine, with iodine monochloride or N-bromo- (or chloro-) succinimide in the presence of sodium azide at 25–45 °C. An efficient, convenient, and benign methodology for C-5 halogenation of pyrimidine-based nucleosides has been developed by using N-halosuccinimides as halogenating reagents without any catalyst but with an expensive ionic liquid medium as a solvent.[17] Moreover, highly regioselective bromination of heteroaromatic compounds has been reported by using N-bromosuccinimide in tetrabutylammonium bromide.[18] Thus, the development of an affordable and simple protocol for efficiently synthesizing 5-halouracil derivatives is an attractive challenge.

To the best of our knowledge, none of the reported syntheses of 5-halouracil derivatives was carried out under microwave conditions in the presence of a heterogeneous catalyst. Herein, we offer a simple and easy preparation of BF₃@K10 and describe its utility in the synthesis of various halo N-heterocycles.

BF₃@K10 was prepared by addition of BF₃·OEt₂ to MMT clay in dichloromethane, followed by evaporation of the solvent under reduced pressure. The catalyst was characterized by different analytical methods, including FTIR and ¹¹B NMR solid-state spectroscopy, XRD, SEM, and EDS. The FTIR bands at 1448 and 1182 cm^–1, assigned to B–O and B–F, respectively, confirm the presence of boron trifluoride.[19] Figure [1] shows the presence of a band at 3620 cm^–1, which is attributed to the vibration of hydroxy groups bound to silicon, aluminum, and magnesium atoms. The bands at 3443, 3231, and 1639 cm^–1 correspond to the elongation and deformation vibrations of the water absorbed by the MMT. In addition, the bands at 528 and 467 cm^–1 correspond to the deformation vibrations of Si–O–Al and Si–O–Si, respectively.[20] A comparison of the IR spectra of the K10 and BF₃@K10 materials reveals that, owing to the impregnation of boron trifluoride into MMT, the position of the strong band at 1048 cm^–1 (stretching vibration of Si–O in tetrahedral sites) has been shifted to 1094 cm^–1.

To confirm the successful impregnation, ¹¹B NMR spectroscopic analyses of MMT and BF₃@K10 were recorded in the solid state. The spectrum of BF₃@K10 shows the presence of a broad signal at around 15 ppm attributable to BF₃ species integrated with Si and Al centers. It is worth noting that no such signal was observed in K10 (Figure [2]).

The XRD patterns of K10 and BF₃@K10 (Figure [3]) reveal similar features, which indicates minimal structural distortion. Basal d001 spacing was observed for both samples at about 2θ ≈ 8.8°, which indicates the presence of a residual 2:1 (T–O–T) structure (two tetrahedral sheets flanking an octahedral layer).[21] Additional reflections at 2θ ≈ 20–30° were attributed to quartz (marked with Q) and cristobalite.[22] Overall, the remarkable similarities between the diffractograms of the samples indicate that the structure of the clay is preserved during the impregnation of BF₃.

SEM analysis (Figure [4]) shows that the crystalline nature of the clay is maintained after impregnation with boron trifluoride, a result that is in accordance with the XRD results. The chemical composition of the K10 and BF₃@K10 materials was determined by semiquantitative analysis by using energy-dispersive X-ray spectrometry coupled with SEM (Figure [5]). EDS analysis of MMT shows the presence of the three sharp peaks related to the elements Al, Si, Mg, and O (Figure [5a]). However, analysis of BF₃@K10 shows two new peaks attributed to the elements B and F in addition to the original peaks. The B and F contents in the clays are 0.17 and 2.76 wt%, confirming the presence of the BF₃ entity. It is important to note that the high observed atomic F/B ratio (around 6) relative to the theoretical one can be explained by the low sensitivity for boron atoms (a light element) in EDS.

Initially, we focused on the optimization of conditions for the iodination of 4-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (1c, 0.2 mmol) by using N-iodosuccinimide (NIS, 0.22 mmol) as an iodine source in acetonitrile (3 mL) as the solvent at 60 °C for 4 h (Table [1]). First, the effect of the catalyst was studied. The use of boron trifluoride diethyl etherate (BF₃·OEt₂) as a catalyst afforded the desired product 5c in 38% yield. During the reaction, substrate 1c was decomposed by the aggressive Lewis acid BF₃·OEt₂. Next, the Lewis acid reactivity was reduced by loading the BF₃·OEt₂ on hydrothermal carbonization (HTC) MMT and K10 MMT to furnish BF₃@HTC and BF₃@K10, respectively. Gratifyingly, the yield was significantly increased when BF₃@K10 was employed (entry 3, Table [1]). No reaction was observed in the absence of the catalyst. The highest yield (98%) for compound 5c was obtained when 60 mg of the BF₃@K10 was used (Figure [6]A). The conventional conditions (stirring at 60 °C) with BF₃@K10 were further compared with activation by microwave (MW) and sonication protocols to study the rate of reaction. Among the three protocols studied, MW offered the best results. Often, MW reactions performed at higher temperature enable a reduction in the total reaction time. Further optimization of the MW reaction indicated that heating the reaction mixture to 100 °C for 10 min furnished highest yield without observed degradation of the starting material (Figure [6]).

Table 1 Catalyst Screening for Halogenation of 1c ^a

Entry	Catalyst	Yieldb (%)
1	BF3OEt2 (0.024 mL)	38
2	BF3@HTC (60 mg)	44
3	BF3@K10 (60 mg)	98
4	K10 (60 mg)	16
5	Without catalyst	0

^a Reaction conditions: 1c (0.2 mmol), NIS (0.22 mmol, 1.1 equiv), acetonitrile (3 mL), 60 °C, 4 h.

^b Yields of isolated products.

With the optimized conditions in hand, we explored the substrate scope for the halogenation (I/Br/Cl) of different uracil derivatives (Scheme [1]). We studied the halogenation of various N-alkylated uracil analogs, including acyclic (ethyl acetate), heterocyclic (2′-deoxyribose), benzylic, and homoanalogous (methyl-1,3,4-oxadiazole) derivatives. The results show that the catalyst is highly efficient in the synthesis of 5-chlorouracil, 5-bromouracil, and 5-iodouracil derivatives 3–5. We noticed that conventional heating and microwave activation furnished similar yields. The halogenation yields varied between 84 and 99%. There was a small decrease in the yield for the formation of nucleoside products 3–5d. We attribute this to cleavage of the glycosidic bond in the presence of acid at elevated temperature. In addition, we performed halogenation of other heterocycles such as a pyrazole, 2-aminopyridine, theophylline, and an imidazo[1,2-a]pyridine by using conventional heating. Halogenation of these heterocycles resulted in the chlorinated, brominated, and iodinated derivatives (6–8a–d; Figure [7]) in good to excellent isolated yields (62–99%). The drop in yield for the pyridine products was a result of the formation of the secondary 3,5-dihalopyridine products.

One of the advantages of heterogeneous catalysis is the ease of separation by filtration and reuse of the catalyst. In this case, efficient recycling is more difficult because the catalyst is not covalently bound to the support. Hence, after the first use, the catalyst was recovered by filtration at the end of the reaction, washed with acetone and dichloromethane, dried at 100 °C for 2 h, and reused in the iodination reaction. The results show that the yields for the formation of product 5c decreased to 72 and 21%, respectively for the first and second reuse cycles. This observation could be explained by the leaching of BF₃ after each use. To confirm this hypothesis, we stirred the BF₃@K10 in acetonitrile at 60 °C for 4 h. The mixture was cooled to room temperature and filtered to remove the solid material. To the filtrate, alkylated uracil 1c and NIS were added and the mixture was heated at 60 °C for 4 h while being stirred. We obtained the iodinated product 5c in 33% yield (Scheme [2]). This experiment shows that BF₃ leaches into the acetonitrile, which decreases the efficiency of the catalyst after each use.

To demonstrate the value of the new BF₃@K10 catalysis method, we compared the latest results for the formation of 5-halouracil analogs with those in the older literature. The original protocol was developed for the N-alkylation of the halouracils (Cl, Br, I),[23] [24] whereas the new protocol utilized N1-alkylated uracils as starting materials that were then halogenated efficiently by using BF₃@K10.[25] Scheme [3] summarizes the yields from these two protocols. Clearly, the new protocol is superior in terms of higher yields and shorter reaction times for the preparation of 5-halouracil derivatives 3–5a and 3–5e.

Prakash and co-workers have reported BF₃-H₂O as an efficient catalyst for halogenating aromatic compounds.[26] Indeed, BF₃-H₂O forms H⁺, which activates the N-halosuccinimide (NXS) to afford X⁺ (scheme 4, eq. 1). To verify this mechanism, K10 MMT was dried at 120 °C for 2 days and used to prepare BF₃@K10. This catalyst was used in the iodination of pyrimidine 1c to give iodopyrimidine 5c in 98% yield, which suggests that BF₃ does not need water to activate NXS. Thus, the proposed mechanism is that BF₃ is adsorbed onto the surface of K10 and reacts as a Lewis acid, activating NXS to form X⁺ (Scheme [4], eq. 2).

In conclusion, the solid clay BF₃@K10 was prepared with K10 as a support, and it was found to be an excellent heterogenous catalyst for the halogenation of N-heterocycles, including pyrimidines, a pyrazole, 2-aminopyridine, theophylline, and an imidazo[1,2-a]pyridine. The interlayer structure of BF₃@K10 enabled efficient chlorination, bromination, and iodination by using N-halosuccinimides as the halogenating source. The key features of this method are short reaction times, high yields, an affordable catalyst, and easy workup. The synthetic methodologies described herein are expected to allow broader access to halogenated heterocyclic compounds for the scientific community.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors would like to thank the technical staff of the Centre of Analysis and Characterization, Cadi Ayyad University, for performing the spectroscopic analyses.

• References and Notes

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• 25 Synthesis of BF₃@K10: K10 clay (1.2 g) was dispersed in dichloromethane (10 mL). Subsequently, BF₃OEt₂ (400 mg) was added dropwise to the mixture at 0 °C under stirring. The mixture was then stirred at room temperature for 1 h, at the end of which the dichloromethane was evaporated under reduced pressure to obtain BF₃@K10. Typical procedure for the transformation of 2-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (1b) with conventional heating: A mixture of pyrimidine 1b (0.2 mmol), N-halosuccinimide (0.22 mmol), and BF₃@K10 (60 mg) in acetonitrile (3 mL) was heated at 60 °C for 4 h. The mixture was then cooled, the catalyst was recovered by filtration and washed with acetone and dichloromethane, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography with a methanol/dichloromethane mixture as the eluent to obtain the corresponding halogenated product 3b. Typical procedure for the transformation of 2-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (1b) with microwave activation: A mixture of pyrimidine 1b (0.2 mmol), N-halosuccinimide (0.22 mmol), and BF₃@K10 (60 mg) in acetonitrile (3 mL) was placed in a closed pressure vessel and heated to 100 °C (400 W) for 10 min in a microwave. The mixture was then cooled, the catalyst was recovered by filtration and washed with acetone and dichloromethane, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography with a methanol/dichloromethane mixture as the eluent to obtain the corresponding halogenated product 3b: R_f = 0.34 (CH₂Cl₂/MeOH, 9.9:0.1); mp 235–237 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.107 (s, 2 H, CH₂), 7.43 (d, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.50 (t, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.83 (t, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.87 (d, ³ J _H-H = 7.6 Hz, 1 H, H_Ph), 8.17 (s, 1 H, H-6), 11.68 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 50.53 (CH₂), 107.62 (C-5), 111.03 (C_Ph), 117.59 (CN), 128.51 (C_Ph), 128.97 (C_Ph), 133.77 (C_Ph), 134.04 (C_Ph), 142.25 (C_Ph), 143.36 (C-6), 150.66 (C-2), 159.92 (C-4). IR (KBr): 3420 (NH), 3041 (Csp2H), 2829 (Csp3H), 2232 (CN), 1694 (C=O), 1243 (Csp2-Cl) cm^–1. HRMS: m/z calcd [M + H]⁺: 262.0383; found: 262.0391.
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Corresponding Author

Publication History

Received: 18 July 2023

Accepted after revision: 16 November 2023

Accepted Manuscript online:
16 November 2023

Article published online:
18 December 2023

© 2023. Thieme. All rights reserved

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• References and Notes

• 1a Kate A, Sahu LK, Pandey J, Mishra M, Sharma PK. Curr. Res. Green Sustainable Chem. 2022; 5: 100248
  CrossrefSearch in Google Scholar
• 1b Singh H, Rajput JK. Sustainable Catalysis . In Encyclopedia of Physical Organic Chemistry . Wang Z. John Wiley & Sons; Hoboken: 2017: 1-40
  Search in Google Scholar
• 2a Varadwaj GB. B, Parida KM. RSC Adv. 2013; 3: 13583
  CrossrefSearch in Google Scholar
• 2b Yaghmaeiyan N, Mirzaei M, Delghavi R. Results Chem. 2022; 4: 100549
  CrossrefSearch in Google Scholar
• 2c Devaraj Naik B, Udayakumar M. Mat. Today: Proc. 2021; 46: 9855
  Search in Google Scholar
• 2d Kaur N, Kishore DJ. Chem. Pharm. Res. 2012; 4: 991
  Search in Google Scholar
• 2e Rambabu G, Kiran YB. R, Tarakeswar Y, Khalivulla SI, Barbosa LC. A, Vijayakumar V. Chem. Biodiversity 2022; 19: e202200669
  CrossrefPubMedSearch in Google Scholar
• 2f Kumar BS, Dhakshinamoorthy A, Pitchumani K. Catal. Sci. Technol. 2014; 4: 2378
  CrossrefSearch in Google Scholar
• 2g García-Guzmán P, Medina-Torres L, Bernad-Bernad MJ, Calderas F, Manero O. Mater. Today Commun. 2023; 35: 105604
  CrossrefSearch in Google Scholar
• 3a Hechelski M, Ghinet A, Louvel B, Dufrénoy P, Rigo B, Daïch A, Waterlot C. ChemSusChem 2018; 11: 1249
  CrossrefPubMedSearch in Google Scholar
• 3b Yaghmaeiyan N, Mirzaei M, Bamoniri A. Arabian J. Chem. 2023; 16: 105026
  CrossrefSearch in Google Scholar
• 4 Li JT, Xing CY, Li TS. J. Chem. Technol. Biotechnol. 2004; 79: 1275
  CrossrefSearch in Google Scholar
• 5 Bordoni C, Cima CM, Azzali E, Costantino G, Brancale A. RSC Adv. 2019; 9: 20113
  CrossrefPubMedSearch in Google Scholar
• 6 Bamoniri A, Mirjalili BB. F, Moshtael-Arani N. J. Mol. Catal. A: Chem. 2014; 393: 272
  CrossrefSearch in Google Scholar
• 7 Mirjalili BB. F, Bamoniri A, Akbari A. Tetrahedron Lett. 2008; 49: 6454
  CrossrefSearch in Google Scholar
• 8 Sadeghi B, Mirjalili BB. F, Hashemi MM. Tetrahedron Lett. 2008; 49: 2575
  CrossrefSearch in Google Scholar
• 9 Bamoniri A, Yaghmaeiyan N, Sajadi SM. Results Chem. 2023; 5: 100870
  CrossrefSearch in Google Scholar
• 10 Taylor, R. 1990.
• 11 De La Mare P. Electrophilic Halogenation: Reaction Pathways Involving Attack by Electrophilic Halogens on Unsaturated Compounds. Cambridge University Press; Cambridge: 1976
  Search in Google Scholar
• 12a Winterton N. Green Chem. 2000; 2: 173
  CrossrefSearch in Google Scholar
• 12b Gribble GW. J. Chem. Educ. 2004; 81: 1441
  CrossrefSearch in Google Scholar
• 12c Fujimori DG, Walsh CT. Curr. Opin. Chem. Biol. 2007; 11: 553
  CrossrefPubMedSearch in Google Scholar
• 13 Metal-Catalyzed Cross-Coupling Reactions and More . De Meijere A, Bräse S, Oestreich M. Wiley-VCH; Weinheim: 2013
  Search in Google Scholar
• 14 Handbook of Grignard reagents . Silverman GS, Rakita PE. CRC Press; Boca Raton: 1996
  Search in Google Scholar
• 15 Asakura J, Robins MJ. J. Org. Chem. 1990; 55: 4928
  CrossrefSearch in Google Scholar
• 16 Kumar R, Wiebe LI, Knaus EE. Can. J. Chem. 1994; 72: 2005
  CrossrefSearch in Google Scholar
• 17 Kumar V, Yap J, Muroyama A, Malhotra SV. Synthesis 2009; 3957
• 18 Ganguly NC, De P, Dutta SJ. S. Synthesis 2005; 1103
  Thieme Connect
• 19 Abdollahi-Alibeik M, Rezaeipoor-Anari A. Catal. Sci. Technol. 2014; 4: 1151
  CrossrefSearch in Google Scholar
• 20 Zeynizadeh B, Rahmani S. RSC Adv. 2019; 9: 28038
  CrossrefPubMedSearch in Google Scholar
• 21 Dharne S, Bokade VV. J. Nat. Gas Chem. 2011; 20: 18
  CrossrefSearch in Google Scholar
• 22 Wu H, Xie H, He G, Guan Y, Zhang Y. Appl. Clay Sci. 2016; 119: 161
  CrossrefSearch in Google Scholar
• 23 El Mansouri A.-E, Zahouily M, Lazrek HB. Synth. Commun. 2019; 49: 1802
  CrossrefSearch in Google Scholar
• 24 El Mansouri A.-E, Maatallah M, Ait Benhassou H, Moumen A, Mehdi A, Snoeck R, Andrei G, Zahouily M, Lazrek HB. Nucleosides, Nucleotides Nucleic Acids 2020; 39: 1088
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• 25 Synthesis of BF₃@K10: K10 clay (1.2 g) was dispersed in dichloromethane (10 mL). Subsequently, BF₃OEt₂ (400 mg) was added dropwise to the mixture at 0 °C under stirring. The mixture was then stirred at room temperature for 1 h, at the end of which the dichloromethane was evaporated under reduced pressure to obtain BF₃@K10. Typical procedure for the transformation of 2-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (1b) with conventional heating: A mixture of pyrimidine 1b (0.2 mmol), N-halosuccinimide (0.22 mmol), and BF₃@K10 (60 mg) in acetonitrile (3 mL) was heated at 60 °C for 4 h. The mixture was then cooled, the catalyst was recovered by filtration and washed with acetone and dichloromethane, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography with a methanol/dichloromethane mixture as the eluent to obtain the corresponding halogenated product 3b. Typical procedure for the transformation of 2-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (1b) with microwave activation: A mixture of pyrimidine 1b (0.2 mmol), N-halosuccinimide (0.22 mmol), and BF₃@K10 (60 mg) in acetonitrile (3 mL) was placed in a closed pressure vessel and heated to 100 °C (400 W) for 10 min in a microwave. The mixture was then cooled, the catalyst was recovered by filtration and washed with acetone and dichloromethane, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography with a methanol/dichloromethane mixture as the eluent to obtain the corresponding halogenated product 3b: R_f = 0.34 (CH₂Cl₂/MeOH, 9.9:0.1); mp 235–237 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.107 (s, 2 H, CH₂), 7.43 (d, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.50 (t, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.83 (t, ³ J _H–H = 7.8 Hz, 1 H, H_Ph), 7.87 (d, ³ J _H-H = 7.6 Hz, 1 H, H_Ph), 8.17 (s, 1 H, H-6), 11.68 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 50.53 (CH₂), 107.62 (C-5), 111.03 (C_Ph), 117.59 (CN), 128.51 (C_Ph), 128.97 (C_Ph), 133.77 (C_Ph), 134.04 (C_Ph), 142.25 (C_Ph), 143.36 (C-6), 150.66 (C-2), 159.92 (C-4). IR (KBr): 3420 (NH), 3041 (Csp2H), 2829 (Csp3H), 2232 (CN), 1694 (C=O), 1243 (Csp2-Cl) cm^–1. HRMS: m/z calcd [M + H]⁺: 262.0383; found: 262.0391.
• 26 Prakash GK. S, Mathew T, Hoole D, Esteves PM, Wang Q, Rasul G, Olah GA. J. Am. Chem. Soc. 2004; 126: 15770
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