N-Benzo[c][1,2,5]thiazol-4-yl-3-trifluoromethylbenzamide

Abstract

The title compound, N-benzo[c][1,2,5]thiazol-4-yl-3-trifluoromethylbenzamide (1) was synthesized by reacting 3-trifluoromethylbenzoyl chloride (4) and 4-aminobenzo[c][1,2,5]thiadiazole (5). The compound was characterized by various spectroscopic methods (¹H NMR, ¹³C NMR, IR, GC-MS) and its composition confirmed by elemental analysis. The importance of this compound lies in its possession of an N,N-bidentate directing group. Such a structural motif is potentially suitable for metal-catalyzed C-H bond functionalization reactions.

1. Introduction

The functionalization of C-H bonds [1,2] transforms an inert nonpolar C-H bond into a reactive/functional one. The strategy can allow the direct access of target molecules, avoiding pre-functionalized materials and/or reagents. Thus materials, reagents, solvents and energy are saved. This concurrently should result in the minimization of waste in a great manifestation of the reduction of waste at the source. Therefore, the functionalization of C-H bonds is atom economical and an environmentally benign approach, and thus green. Site-selectivity or regioselectivity is a major issue in the science of C-H bond functionalization. One approach to improve the site-selectivity is to use directing groups that contain Lewis basic atoms to coordinate the Lewis acidic metal facilitating the C-H bond cleavage. Directing groups can contain one Lewis basic atom, as in monodentate directing groups [3], or two Lewis basic atoms, as in bidentate directing groups [3,4]. The required chelation assistance by directing groups can be designed. The underlying principle is the thermodynamic stability of the intermediate five-membered chelates [4]. Therefore, that was a strong incentive for the synthesis of compounds bearing the more efficient bidentate directing groups. Toward that end, the title compound is synthesized. The title compound, N-benzo[c][1,2,5]thiazol-4-yl-3-trifluoromethylbenzamide (1, Scheme 1), possessing two nitrogen (N) atoms separated by two carbons, represents an example of the N,N-bidentate directing group [5]. Thus, it is potentially a substrate for metal-catalyzed C-H bond functionalization. Therefore, the title compound possessing the requisite N,N-bidentate directing group can undergo cyclometallation to give an intermediate double-five membered chelate (2) followed by a reaction with a suitable electrophile to give the final C-H functionalized product (3, Scheme 1).

The efficacy of 4-aminobenzo[c][1,2,5]thiadiazole (5) as a bidentate directing group has been recently reported by Babu et al. [6]. Thus, amides bearing the directing group have been reported to undergo the Pd-catalyzed β–C(sp³)-H bond arylation/acetoxylation of aliphatic and alicyclic carboxamides. The thiadiazole group also affects the C(sp²)-H arylation/benzylation/acetoxylation/alkoxylation of benzamides bearing the amine [6]. It is part of our research program to develop new directing groups potentially suitable for C-H functionalization. Thus we synthesize various amides bearing various N,N-bidentate directing groups. We employ benzoyl chlorides that are differently substituted with various groups that are electronically different and in various positions. The CF₃ electron-withdrawing group (EWG) is chosen amongst other EWG groups and electron-donating group (EDG) counterparts to study the influence of groups on substrates in metal-catalyzed C-H bond functionalization. Thus, the title compound N-benzo[c][1,2,5]thiazol-4-yl-3-trifluoromethylbenzamide (1, Scheme 1) possessing the requisite N,N-bidentate directing group is synthesized. The synthesis is achieved using a simple yet effective protocol

2. Results

Toward the synthesis of the title compound N-benzo[c][1,2,5]thiazol-4-yl-3-trifluoromethylbenzamide (1), 3-trifluoromethylbenzoyl chloride (4) was reacted with 4-aminobenzo[c][1,2,5]thiadiazole (5) in a typical amide synthesis protocol (Scheme 2). Both reaction partners are commercially available and used as purchased from chemical vendors. The nucleophilic acyl substitution reaction was facilitated by the addition of triethylamine (Et₃N) (Scheme 2).

The product obtained in a 90% yield (Scheme 2) and was characterized by various spectroscopic methods. ¹H NMR (Figure S1), ¹³C NMR (Figure S2, supporting information), IR (Figure S3, supporting information), GC-MS (Figure S4, supporting information) and its elemental composition were confirmed by measured elemental analysis (Figure S5, supporting information).

For comparison purposes, the target compound (1) was also obtained using a different method. Thus the 3-trifluoromethylbenzoic acid (6, Scheme 3) was treated with the coupling agent EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) and 4-aminobenzo[c][1,2,5]thiadiazole (5) in the presence of DMAP (4-N,N-dimethylaminopyridine) to give the desired title compound (1) in a 46% yield.

In addition, the target compound was obtained by treating the starting carboxylic acid, 3-trifluoromethylbenzoic acid (6, Scheme 4), with oxalyl chloride in the presence of DMF, followed by the treatment of the resultant acid chloride with 4-aminobenzo[c][1,2,5]thiadiazole (5). The desired amide product (1) was obtained in a 61% yield.

The benzoic acid-amine coupling method illustrated above (Scheme 3) and the starting acid transformation via the acid chloride (Scheme 4) required longer reaction times and resulted in lower yields. Therefore, the present method, starting from the acid chloride (Scheme 2), outweighs the alternative methods in terms of time and yield and thus efficiency, despite the relatively higher cost of the acid chloride (relative to the benzoic acid).

3. Materials and Methods

3.1. General Methods

All chemicals, reagents and solvents were purchased from chemical companies (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany) and were used as received without prior purification. Reactions that required dry conditions were performed in an inert atmosphere with Ar gas. Syringes and needles for the transfer of reagents were oven dried and cooled in a desiccator over silica gel before use. The reaction’s progress was monitored by thin-layer chromatography (TLC) on glass plates pre-coated with Merck silica gel. TLC plates were examined under UV lamplight (UVGL-58 Handheld 254/365 nm). Büchi-USA rotary evaporators were used to evaporate solvents using appropriate temperatures. Flash column chromatography was performed using silica gel (Kieselgel) (70–230) mesh as an adsorbent. The purified products were characterized using analyses NMR (¹H NMR, ¹³C NMR), IR, mass spectra and melting points. Melting points were recorded on the GallenKamp-MPd350.bm2.5 melting point apparatus (Gallenkamp, Kent, UK). Attenuated total-reflectance IR spectra were recorded on pure samples on Agilent Technologies Cary 630 FTIR (Agilent, Santa Clara, CA, USA). ¹H NMR spectra were recorded in CDCl₃ on JEOL ECX-400 spectrometers (JEOL Ltd., Tokyo, Japan). ¹H NMR chemical shifts (δ) were assigned in part per million (ppm) downfield using an internal standard trimethylsilane (TMS) and were referenced to CDCl₃, δ = 7.24. Abbreviations s, d, t, q, quin, sept and m refer to singlet, doublet, triplet, quartet, quintet, septet and multiplet, respectively. Chemical shifts in ¹³C spectra (175 MHz) were quoted in ppm and referenced to the central line of the CDCl₃ triplet, δ C 77.0. Coupling constants (J) were recorded in hertz (Hz). GC-MS spectra were obtained using an Agilent mass spectrometer (Agilent, Santa Clara, CA, USA). Elemental analysis was performed using an EuroEA Elemental Analyzer (configuration CHN (EuroVector Instruments & Software, Milano, Italy) with a calibration type of K-factor.

3.2. Synthesis of N-benzo[c][1,2,5]thiazol-4-yl-3-trifluoromethylbenzamide (1)

3-Trifluoromethylbenzoyl chloride (4) (1.00 mL, 6.63 mmol) was added dropwise under an atmosphere of N₂ into a cold (0 °C ice-water bath) solution of 4-aminobenzo[c][1,2,5]thiadiazole (5) (1.11 g, 7.34 mmol), in CH₂Cl₂ (50 mL). Et₃N (3.00 mL, 21.5 mmol) was then added to the 0 °C mixture under N₂. The mixture was stirred for 1 h at 0 °C, allowed to warm up to room temperature and then stirred for an additional 5 h. To the reaction mixture, aqueous saturated NaHCO₃ solution (50 mL) was added. The mixture was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic extracts were dried over anhydrous MgSO₄ and filtered. The evaporation of the solvents under reduced pressure followed by flash chromatography (SiO₂) using Petroleum ether:Et₂O (9:1) gave the title compound (1) as a silver crystalline solid after recrystallization from CH₂Cl₂:hexane (1.92 g, 90%). R_f = 0.63 (Pet. Ether:EtOAc (1:1)), mp = 99–101 °C. ¹H NMR (700 MHz, CDCl₃): δ = 9.21(s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.25 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.64 (m, 2H). ¹³C NMR (176 MHz, CDCl₃): δ = 164.0, 154.7, 147.9, 135.0, 131.8 (q, J_C-F = 271 Hz), 131.0, 130.2, 129.6 (q, J_C-F = 14), 128.9 (q, J_C-F = 4), 124.9, 124.5 (q, J_C-F = 9 Hz), 122.2, 116.4, 115.5. IR(film): νmax/cm⁻¹: 3293, 1651, 1545, 1522, 1482, 1434. MS (EI) m/z (relative intensity): 323 (16), 173 (100), 145 (67), 125 (6), 95 (12), 75 (6). Elemental analysis, calculated: C (52.01), H (2.49), N (13.00), found (average of two runs): C (51.822), H (2.339), N (12.700).